Retrieval of Medicinal Chemical Information

Retrieval of Medicinal Chemical Information W. Jeffrey Howe, EDITOR The Upjohn Company Margaret M. Milne, EDITOR Smi...

Author: W. Jeffrey Howe | Margaret M. Milne | Ann F. Pennell

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Retrieval of Medicinal Chemical Information W. Jeffrey Howe,

EDITOR

The Upjohn Company Margaret M. Milne,

EDITOR

Smith, Kline, and French An ICI Americas, Inc.

Based on a symposium cosponsored by the Divisions of Computers i n Chemistry and Chemical Information at the 175th Meeting of the American Chemical Society, Anaheim, California, March 13-17, 1978.

ACS SYMPOSIUM SERIES 84

AMERICAN

CHEMICAL

SOCIETY

WASHINGTON, D. C. 1978

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

Library of Congress Œ ? Data Symposium on Retrieval of Medicinal Chemical Information, Anaheim, Calif., 1978. Retrieval of medicinal chemica (ACS symposium series; 84 ISS Based on a symposium cosponsored by the Divisions of Computers in Chemistry and Chemical Information at the 175th meeting of the American Chemical Society, California, March 1978. Includes bibliographies and index. 1. Information storage and retrieval systems—Chemistry, Pharmaceutical—Congresses. 2. Chemistry, Pharmaceutical—Data processi ng—Congresses. I. Howe, William Jeffrey, 1946- . II. Milne, Margaret M., 1946- . III. Pennell, Ann R, 1946- . IV. American Chemical Society. Division of Computers in Chemistry. V. American Chemical Society. Division of Chemical Information. VI. Title. VII. Series: American Chemical Society. ACS symposium series; 84. RS421.S93 1978 615Μ9Ό2854 78-21611 ISBN 0-8412-0465-9 ACSMC 8 84 1-231 1978

Copyright © 1978 American Chemical Society All Rights Reserved. The appearance of the code at the bottom of thefirstpage of each article in this volume indicates the copyright owner's consent that reprographic copies of the article may be made for personal or internal use or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc. for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Law. This consent does not extend to copying or transmission by any means—graphic or electronic—for any other purpose, such as for general distribution, for advertising or promotional purposes, for creating new collective works, for resale, or for information storage and retrieval systems. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by ACS of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, specification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission, to the holder, reader, or any other person or corporation, to manufacture, repro duce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. PRINTED IN THE UNITED

STATES

OF

AMERICA

Society Library 1155 16th St. N. W. In Retrieval of Medicinal Chemical Information; Howe, W., et al.; Washington, D. C. Society: 20036Washington, DC, 1978. ACS Symposium Series; American Chemical

ACS Symposium Series Robert F. Gould, Editor

Advisory Board Kenneth B. Bischoff

Nina I. McClelland

Donald G. Crosby

John B. Pfeiffer

Jeremiah P. Freeman

Joseph V. Rodricks

E. Desmond Goddard

F. Sherwood Rowland

Jack Halpern

Alan C. Sartorelli

Robert A. Hofstader

Raymond B. Seymour

James P. Lodge

Roy L. Whistler

John L. Margrave

Aaron Wold

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

FOREWORD The ACS SYMPOSIUM SERIES was founded in 1974 to provide a medium for publishin format of the Series parallels that of the continuing ADVANCES IN CHEMISTRY SERIES except that in order to save time the papers are not typeset but are reproduced as they are submitted by the authors in camera-ready form. Papers are reviewed under the supervision of the Editors with the assistance of the Series Advisory Board and are selected to maintain the integrity of the symposia; however, verbatim reproductions of previously published papers are not accepted. Both reviews and reports of research are acceptable since symposia may embrace both types of presentation.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

PREFACE '""phe symposium on retrieval of medicinal chemical information was organized to examine current developments in the storage, retrieval, and manipulation of the variety of types of data that are associated with medicinal chemistry in the pharmaceutical industry, government agencies, and related organizations. This volume contains expanded versions of the papers presented at the symposium as well as several additional invited papers. To insure adequate coverage of what has become a broad and increasingly important field, the speakers were selected to approach the topic from a number of differen the manipulation of biological data, chemical substructure searching, computer graphical display of retrieved data, the integration of biological search results with chemical information, the utilization of retrieval systems in the research function, mathematical analyses of chemical-structure data bases, and so on. While some of the chapters deal with commercially available information systems, most focus on the capabilities of systems that were developed within individual organizations. Authors were encouraged to include not only what has been done in the area, but what is now being planned for implementation in the near future to meet the growing information needs of medicinal chemical research. Several papers have been included that were not presented at the symposium. These invited submissions extend the treatment of the subject beyond the limitations of a one-day symposium. However, the breadth of thefieldof medicinal chemical information has made it impossible to offer complete coverage in a volume of this size. For example, the storage and retrieval of clinical test data is one important area which could not be dealt with here. Early in the planning stages of the symposium it was recognized that some form of overview of medicinal chemical information would be a valuable addition to a proceedings volume. To that end we have written an introductory chapter, based on the contents of the symposium presentations and on discussions with symposium participants. It is hoped that this overview will do three things: (a) provide a fairly complete statement of the current status and directions of progress of the field as a whole, (b) illustrate the interrelationship of the various categories of medicinal chemical information, including those important areas which could not be dealt with in the symposium, and (c) provide a conceptual framework for viewing the material discussed in the papers which follow. A

vii In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

One other point deserves mention. The ACS Books Department has instituted a policy of peei review for papers included in the ACS Symposium Series. Although this adds time and effort to the publication process, it can only result in an improvement in the quality of the papers, and will benefit both readers and authors. We fully support this move. We wish to thank the officers of the Divisions of Chemical Information and Computers in Chemistry for their assistance, especially Gabrielle Revesz, Mary Reslock, and Ed Olson. The Upjohn Company Kalamazoo, MI 49001

W.

Smith, Kline, and French

JEFFREY HOWE

MARGARET M. MILNE

Philadelphia, PA 19101 ICI Americas, Incorporated Wilmington, DE 19897

ANN F. PENNELL

August 22, 1978

viii In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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R e t r i e v a l of M e d i c i n a l C h e m i c a l I n f o r m a t i o n — a n Overview MARGARET M. MILNE—Smith, Kline, and French, Philadelphia, PA 19101 ANN F. PENNELL—ICI Americas, Inc., Wilmington, DE 19897 W. JEFFREY HOWE—The Upjohn Company, Kalamazoo, MI 49001

The following pape writte by the organizers of the ACS Symposium on Retrieval based in part on the Symposium presentations, on discussions with sympusium paticipants, and on the author's own involvement in the field of pharmaceutical research and development. Traditionally, the term "medicinal chemistry" has connoted an area of synthetic organic chemistry which deals with the prepara tion of molecules likely to have some desired physiological re sponse. Associated with each synthesized molecule is a collection of in vivo or in v i t r o test results used to ascertain the actual nature and extent of the bioactivity (if any). Evolving in par a l l e l with this view, medicinal chemical information systems have commonly been based on a data f i l e organized by compound and have contained such items as chemical structure, identification number, source, and sometimes physical properties. The biological test results were also organized by compound, but either because of their volume or for administrative reasons the results were usual ly separate from the structural data f i l e . Over the past 15 years considerable effort has been invested in computerizing these f i l e s , in developing efficient, powerful, and rapid mechanisms for selective r e t r i e v a l , and in integrating the searching of struc tural data with that of biological data without actually combining the individual f i l e s . More recently, however, i t has been recognized that the t r a ditional view of medicinal chemistry is actually one element of a much larger set of functions in the total drug development proc ess. These functions are interrelated and at times interdepend ent, and the drug development process can be made markedly more effective by f a c i l i t a t i n g the necessary interactions. What this implies to developers and users of medicinal chemical information systems is a need for access to a considerably more diverse set of drug-related information types and for additional capabilities in retrieving, correlating, and displaying these data. This, in fact, is the direction of current progress in the field of medici0-8412-0465-9/78/47-084-001$05.00 © 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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n a l chemical i n f o r m a t i o n . To examine t h i s progress i n more det a i l , the i n d i v i d u a l f u n c t i o n s that comprise the t o t a l drug development process and the corresponding i n f o r m a t i o n needs w i l l now be considered. The Drug Development Process Figure 1 i l l u s t r a t e s s c h e m a t i c a l l y a h y p o t h e t i c a l drug development program. The diagram i s approximate s i n c e the sequence of f u n c t i o n s may vary somewhat between d i f f e r e n t o r g a n i z a t i o n s and s i n c e not a l l of the conceivable i n t e r a c t i o n s among f u n c t i o n s are i n d i c a t e d . I n a d d i t i o n , some of the f u n c t i o n s may overlap (e.g., p a t h o l o g y / t o x i c o l o g y s t u d i e s may continue d u r i n g c l i n i c a l t r i a l s ) and some may be done i n segments i n t e r l e a v e d among the other f u n c t i o n s (e.g., a p p l i c a t i o n s f o r Food and Drug A d m i n i s t r a t i o n (FDA) approval ma variou diagram does i n c l u d e a l imate r e l a t i o n s h i p s . Development of a drug begins w i t h s e l e c t i o n of a prototype or lead compound or compound s e r i e s whose a c t i v i t y i s t o be o p t i mized. Commonly an o r g a n i z a t i o n such as a pharmaceutical company has c e r t a i n major areas of i n t e r e s t (e.g., a n t i m i c r o b i a l s , cont r a c e p t i v e s , e t c . ) w i t h i n which new lead s t r u c t u r e types are sought. For each such area of i n t e r e s t , a set of b i o l o g i c a l t e s t s o r screens i s designed s p e c i f i c a l l y t o t e s t f o r the d e s i r e d a c t i v i t y . The lead compounds are normally found e i t h e r through random t e s t i n g i n these screens of d i v e r s e chemical types or through ideas t r i g g e r e d by p u b l i c or in-house l i t e r a t u r e . The s e l e c t e d lead i s then developed by a c y c l i c process i n which analogs are s y n t h e s i z e d and bioassayed, r e s u l t s are anal y z e d , and new analogs p o s t u l a t e d t o have even g r e a t e r a c t i v i t y are proposed f o r s y n t h e s i s . This i s the t r a d i t i o n a l realm of m e d i c i n a l chemistry and the area i n which most of the work on m e d i c i n a l chemical i n f o r m a t i o n r e t r i e v a l has been done. Novel compounds s y n t h e s i z e d i n the analog e v a l u a t i o n may be patented a t any p o i n t , and f o r p a r t i c u l a r l y promising compounds, a d d i t i o n a l analogs may be prepared f o r patent p r o t e c t i o n . Compounds t h a t show p a r t i c u l a r l y good a c t i v i t y i n the p r i mary b i o l o g i c a l screening t e s t s are submitted t o pathology, t o x i cology, and pharmacology s t u d i e s to f u r t h e r d e f i n e t h e i r s u i t a b i l i t y as drugs. For those that show promise f o r c l i n i c a l use app r o p r i a t e f o r m u l a t i o n s are developed. When a compound s a t i s f a c t o r y i n a l l of these areas has been found, a request ( I n v e s t i g a t i o n New Drug a p p l i c a t i o n , o r IND) t o t e s t the drug i n humans i s submitted t o FDA summarizing a l l e x i s t i n g data on the compound. More or l e s s c o n c u r r e n t l y , process development s t u d i e s are undertaken t o optimize the manufacturing process and f o r patent prot e c t i o n . Marketing i m p l i c a t i o n s may a l s o be considered i n further d e t a i l at this point. When the IND a p p l i c a t i o n i s approved, c l i n i c a l t r i a l s can be

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

Figure 1.

LEAD SELECTION oMASS SCREENING oLITERATURE

MANAGEMENT

MARKETING

MANUFACTURING r

*

CLINICAL TRIALS

FDA APPLICATION (IND)

FDA APPLICATION (NDA)

PROCESS DEVELOPMENT

FORMULATION

PHARMACOLOGY

PATHOLOGY/ TOXICOLOGY

Major functions in a typical drug-development program

POST MARKETING MONITORING

PATENT

BIOASSAY (LEAD DEVELOPMENT)

REGULATORY A F F A I R S

EVALUATION/ PREDICTION

ANALOG SYNTHESIS AND CHEMICAL ANALYSIS

-I, INVENTORY h —

PUBLICATION

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RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

i n i t i a t e d . Concurrently, manufacturing f a c i l i t i e s and a marketing program are e s t a b l i s h e d . I f the c l i n i c a l t e s t i n g i s successf u l , the r e s u l t s are submitted to the FDA along w i t h a New Drug A p p l i c a t i o n (NDA) requesting approval of the drug f o r use i n the general p o p u l a t i o n . F i n a l l y , once the product i s on the market, i t s use i s monitored to detect any a d d i t i o n a l i n d i c a t i o n s of use or adverse e f f e c t s t h a t may not have been evident during o r i g i n a l testing. In a d d i t i o n to these d i r e c t e d f u n c t i o n s , three types of f u n c t i o n s e x i s t which pervade e s s e n t i a l l y a l l of the other funct i o n s of Figure 1: (1) the management f u n c t i o n i n which d e c i s i o n s are made to determine which p r o j e c t s or compounds w i l l progress, which w i l l be delayed or terminated; (2) the p u b l i c a t i o n f u n c t i o n i n which r e s u l t s are provided to the i n t e r n a l and open l i t e r a t u r e ; and (3) the f u n c t i o n of responding to government regulations r e l a t i n g t Information Needs Related to the Drug Development Process Development of a safe and u s e f u l drug, which i s the u l t i m a t e goal of m e d i c i n a l chemistry, i s an extremely complex and c o s t l y process. The purpose of m e d i c i n a l chemical i n f o r m a t i o n r e t r i e v a l i s to support t h i s process, to permit r a p i d and accurate i d e n t i f i c a t i o n of c l i n i c a l l y u s e f u l compounds w i t h minimal r i s k , c o s t , or delay. The types of i n f o r m a t i o n r e q u i r e d to provide t h i s support are extensive and d i v e r s e . The exact types of data needed w i l l be discussed i n more d e t a i l l a t e r , but some g e n e r a l i z a t i o n s can be made about the way the data must be used. The b a s i c data f u n c t i o n s r e q u i r e d are i n f o r m a t i o n storage, r e t r i e v a l , a n a l y s i s , and r e p o r t i n g . The o r g a n i z a t i o n of the data i n t o v a r i o u s f i l e s must be balanced f o r maximum e f f i c i e n c y . A l though each of the f u n c t i o n s of Figure 1 has i t s own primary i n t e r e s t i n f o r m a t i o n , many s i t u a t i o n s r e q u i r e the combined use of data from d i f f e r e n t areas. For example, the management, p u b l i s h i n g , and r e g u l a t o r y a f f a i r s f u n c t i o n s r e q u i r e access to n e a r l y a l l of the data types at one p o i n t or another. Thus, w h i l e the data must be segmented to a l l o w e f f i c i e n t access by i t s prime users, i n t e r f a c e s must be provided to s a t i s f y c r o s s - f u n c t i o n a l needs as w e l l . The q u a l i t y of the data i s a v i t a l c h a r a c t e r i s t i c . " Q u a l i t y " here encompasses not only accuracy, but comprehensiveness ( i n c l u s i o n of o l d and new data) and s u i t a b i l i t y ( p r o v i d i n g the exact type of data needed r a t h e r than some nebulous f u n c t i o n or q u a l i t a t i v e estimate t h e r e o f ) . Comprehensiveness i s p a r t i c u l a r l y important where chemicals w i t h human b i o a c t i v i t y are being prepared. Procedures f o r using the system should be as a t t r a c t i v e and as simple as p o s s i b l e to encourage d i r e c t use by s p e c i a l i s t s w i t h i n each f u n c t i o n who may not a l s o be i n f o r m a t i o n s p e c i a l i s t s . I n t e r a c t i v e o p e r a t i o n , simple commands, f l e x i b l e outputs t h a t are

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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f a m i l i a r t o the user (such as standard t e x t r a t h e r than computer codes, standard s t r u c t u r a l diagrams r a t h e r than l i n e a r n o t a t i o n s ) a l l help t o get the i n f o r m a t i o n d i r e c t l y i n t o the hands of the i n d i v i d u a l s best equipped t o use i t . Although the p r o v i s i o n of i n t e r f a c e s s u i t a b l e f o r non-computer s p e c i a l i s t s adds c o n s i d e r a b l y to system development and o p e r a t i o n a l c o s t s , these costs should be f a r outweighed by the r e s u l t i n g i n c r e a s e i n e f f e c t i v e n e s s of the t o t a l program. (Of course, some f u n c t i o n s are s t i l l unavoidably complex and w i l l r e q u i r e i n t e r m e d i a t i o n by an i n f o r m a t i o n s p e c i a l i s t f o r the f o r s e e a b l e f u t u r e . ) O r g a n i z a t i o n and Current Status of M e d i c i n a l Chemical Information The major data types r e q u i r e d f o r m e d i c i n a l chemistry as p a r t of a t o t a l drug development program are i n d i c a t e d i n Figure 2. I n this conceptualizatio around the chemical compound ber ( g e n e r a l l y an i n t e r n a l r e g i s t r y number). Four c a t e g o r i e s of data are d e f i n e d : chemical data and b i o l o g i c a l data, which chara c t e r i z e the compound i t s e l f , management/distribution data which c h a r a c t e r i z e the commercial aspects of the compound, and secondary or b i b l i o g r a p h i c data which i n essence are p o i n t e r s t o chemical, b i o l o g i c a l , or management/distribution data i n the open (or occasionally, internal) literature. (a) Chemical Data. V i r t u a l l y a l l o r g a n i z a t i o n s t h a t support a major drug development e f f o r t have a computerized f i l e of the chemical s t r u c t u r e s considered i n the program. F i l e s on the order of 100,000 - 400,000 s t r u c t u r e s are not uncommon. The s t r u c t u r e s are represented as e i t h e r connection t a b l e s , l i n e n o t a t i o n s , o r a t t r i b u t e codes. At present the f i l e s are used f o r s e v e r a l purposes, the most common of which are (a) d u p l i c a t e checking t o determine i f a compound has already been t e s t e d , (b) s u b s t r u c t u r e searching to s e l e c t i v e l y r e t r i e v e compound c l a s s e s , and (c) d i s play of two dimensional s t r u c t u r a l diagrams. Of the chemical data c a t e g o r i e s i n F i g u r e 2 the molecular s t r u c t u r e r e p r e s e n t a t i o n has r e c e i v e d by f a r the g r e a t e s t emphasis i n c u r r e n t i n f o r m a t i o n systems. The other data types ( a n a l y t i c a l , physicochemical, process development, s y n t h e s i s / r e a c t i v i t y ) have been d e a l t w i t h i n d i v i d u a l l y , but are only beginning to be i n c o r porated w i t h the s t r u c t u r e f i l e s t o form i n t e g r a t e d systems. (b) B i o l o g i c a l Data. V i r t u a l l y a l l major m e d i c i n a l chemical i n f o r m a t i o n systems have automated f i l e s which c o n t a i n the primary t e s t i n g r e s u l t s . Because of the importance of c o r r e l a t i n g and coo r d i n a t i n g b i o l o g i c a l data w i t h s t r u c t u r a l data i n the analog development c y c l e , automated l i n k s between the s t r u c t u r e data and primary t e s t i n g data have been provided i n some systems. However, the sheer volume of the b i o l o g i c a l t e s t r e s u l t s (and i n some cases, a d m i n i s t r a t i v e c o n s i d e r a t i o n s ) has c o n t r i b u t e d t o the slow

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

Figure 2. The medicinal chemical information network. The types of data required in a total drug-development process can be viewed as organized around the compounds tested, with four associated categories of data: chemical, biological, management/distribution, and secondary.

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Information

7

progress i n t h i s area. I n many systems the i n t e r f a c e between the two data f i l e s i s e i t h e r u n w i e l d l y o r n o n e x i s t e n t . As was the case w i t h chemical data, the remaining forms of b i o l o g i c a l i n f o r m a t i o n ( t o x i c o l o g y , pathology, pharmacology, c l i n i c a l , f o r m u l a t i o n ) have a l l undergone a c e r t a i n degree of automation, but the extent t o which these data are i n t e g r a t e d w i t h chemical s t r u c t u r e s and primary screening data v a r i e s cons i d e r a b l y . As noted above, a major c o n s t r a i n t appears t o be the volume of data t h a t must be encompassed by these b i o l o g i c a l s y s tems. I n t e r f a c i n g them w i t h each other and w i t h chemical i n f o r mation f o r purposes of r e t r i e v a l can place a heavy burden on even very l a r g e computer systems. As a r e s u l t , users must commonly r e l y on manual methods f o r c o o r d i n a t i n g the data from d i f f e r e n t areas. (c) Management/Distribution p o r t i o n of the m e d i c i n a c a t e g o r i e s of data which a r e extremely important t o the o p e r a t i o n of an e f f e c t i v e drug development program. The d i f f e r e n c e s between e x i s t i n g systems are g r e a t e s t i n t h i s area, i n terms of the data types t h a t are handled and the c a p a b i l i t i e s and i n t e r f a c e s to the r e s t of the network that are provided. Some o f these data types (e.g., i n v e n t o r y and compound sources) are g e n e r a l l y automated and w e l l - i n t e g r a t e d w i t h the chemical and b i o l o g i c a l data. Patent i n f o r m a t i o n on in-house compounds may be automated but i s not commonly l i n k e d d i r e c t l y to the chemical and b i o l o g i c a l data. Manufacturing i s u s u a l l y a separate i n f o r m a t i o n category, not l i n k e d t o the r e s t of the system. Except i n s p e c i a l cases, such as manufacturing problems r e l a t e d t o the chemistry of a p a r t i c u l a r process, t h i s s e p a r a t i o n i s reasonable a t present. Marketing i s another area which c u r r e n t l y appears t o be d i vorced from the r e s t of the network. The importance of market a n a l y s i s (both before and a f t e r approval of a product) as an i n t e g r a l p a r t of the drug development e f f o r t i s becoming i n c r e a s i n g l y apparent. Such a n a l y s i s i s v i t a l d u r i n g lead s e l e c t i o n t o determine what products are needed, during process development t o guarantee reasonable manufacturing c o s t s (where "reasonable" i s r e l a t e d t o the drug's market), and d u r i n g the i n i t i a l stages of p u b l i c use t o respond t o any e f f e c t s t h a t may not have been e v i dent during t e s t i n g . One of the most a c t i v e areas i n the handling o f m e d i c i n a l chemical i n f o r m a t i o n i s concerned w i t h the requirements of government r e g u l a t o r y agencies. This i n c l u d e s i n f o r m a t i o n r e quired not only f o r purposes o f drug approval but a l s o t o comply w i t h r e g u l a t i o n s concerning the environmental e f f e c t s of the manu f a c t u r i n g process and the h e a l t h and s a f e t y of i n d i v i d u a l s exposed t o chemicals i n any phase of the drug development process. In many o r g a n i z a t i o n s major e f f o r t s a r e now being undertaken t o i n c o r p o r a t e h e a l t h , s a f e t y , and environmental data i n t o the t o t a l chemical i n f o r m a t i o n network.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

8

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

(d) Secondary Data, Almost a l l drug development o r g a n i z a t i o n s u t i l i z e one or more of the major o n l i n e i n f o r m a t i o n s e r v i c e s f o r r e t r o s p e c t i v e and current awareness l i t e r a t u r e review. I n add i t i o n , in-house i n f o r m a t i o n groups are o f t e n r e s p o n s i b l e f o r r e viewing the current l i t e r a t u r e on s p e c i f i c problems. Most c a t e g o r i e s of data that are c u r r e n t l y r e t r i e v a b l e through the o n l i n e s e r v i c e s are t e x t o r i e n t e d (such as a b s t r a c t s , keywords, and patent d a t a ) , however i n c r e a s i n g l y more s p e c i a l i z e d data types are being o f f e r e d , such as p h y s i c a l constants, r e a c t i o n s , b i o l o g i c a l data (e.g., LD50), and substructure i n f o r m a t i o n . Some i n t e g r a t i o n of these f i l e s e x i s t s , though a t present the i n t e g r a t i o n i s p r i m a r i l y w i t h i n a s i n g l e i n f o r m a t i o n assembling o r g a n i z a t i o n . Nevertheless, there appears to be a growing r e c o g n i t i o n of the need f o r i n t e r f a c i n g and c o m p a t i b i l i t y even among competing s e r v ices . Government supporte of p u b l i c i n f o r m a t i o n . respond to government r e g u l a t i o n s as w e l l as to a s s i s t t e c h n i c a l researchers. Data bases c o n t a i n i n g s t r u c t u r e s of p e r t i n e n t compounds (e.g., r e g u l a t e d drugs, carcinogens, t o x i c compounds) are r a p i d l y being b u i l t , and sometimes i n c o r p o r a t e a d d i t i o n a l u s e f u l chemical i n f o r m a t i o n such as c r y s t a l l o g r a p h i c and s p e c t r a l data. An i n t e r e s t i n g s i d e e f f e c t to the development of these f i l e s has been the encouragement of c o m p a t i b i l i t y among p r i v a t e systems. This has r e s u l t e d because a number of p r i v a t e o r g a n i z a t i o n s are seeking uniform methods of accessing in-house and p u b l i c f i l e s and have standardized on the format of the p u b l i c systems. Future Trends i n M e d i c i n a l Chemical Information While the f o l l o w i n g chapters i n t h i s book present a comprehensive view of the current c a p a b i l i t i e s of m e d i c i n a l chemical i n formation systems, they a l s o provide i n s i g h t s i n t o the d i r e c t i o n s of progress of the f i e l d as a whole. The foremost trend i s toward i n t e g r a t i o n : the p u l l i n g t o gether of d i s c r e t e in-house systems and the c r e a t i o n of automated i n t e r f a c e s t o p u b l i c and government systems along the l i n e s of the i n f o r m a t i o n network i n Figure 2. Much of the stimulus f o r i n t e g r a t i o n comes from the c r o s s - d i s c i p l i n a r y nature of the t e c h n i c a l i n f o r m a t i o n needs (such as the need f o r simultaneous access to chemical and b i o l o g i c a l data i n the analog development p r o c e s s ) . At the same time, as the i n f o r m a t i o n systems become more encompassing and more responsive to the t e c h n i c a l needs, they are ena b l i n g better-informed and more coordinated management d e c i s i o n s at higher l e v e l s . Such support of the management f u n c t i o n i s expected g r a d u a l l y to become more formal, o f f e r i n g management s p e c i f i c r e p o r t i n g and i n q u i r y c a p a b i l i t i e s w i t h simultaneous access t o a l l types of data on demand. Another extremely important trend i s toward greater end-user o r i e n t a t i o n . This area was somewhat neglected w h i l e system de-

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

1.

MILNE ET AL.

Medicinal

Chemical

Information

9

velopment e f f o r t s focused on techniques f o r data storage and r e t r i e v a l . The emphasis on end-users i s evident i n the increased a p p l i c a t i o n of computer graphics t o the user-computer i n t e r f a c e and i n the growing number of i n t e r a c t i v e systems. Greater f l e x i b i l i t y i n adapting t o s p e c i a l i z e d needs i s apparent not only i n the v a r i e t y of data types and data manipulations t h a t are poss i b l e , but a l s o i n the o r g a n i z a t i o n and r e o r g a n i z a t i o n of outputs to permit data t o be examined from many s t a n d p o i n t s . The r e t r i e v e d data i s more end-user o r i e n t e d i n order t o be interprétable without cumbersome lookup t a b l e s o r other a r t i f a c t s of comp u t e r i z a t i o n . O v e r a l l , the apparent o b j e c t i v e i s to make i n f o r mation systems a working t o o l of the i n d i v i d u a l s best equipped t o use them, r a t h e r than a reference u t i l i t y a c c e s s i b l e only through the i n f o r m a t i o n s p e c i a l i s t . Now t h a t automated r e t r i e v a l i s w e l l e s t a b l i s h e d , e f f o r t s are f o c u s i n g on automate r a t e s t a t i s t i c a l and h e u r i s t i cated f u n c t i o n s such as quantum mechanics and conformational anal y s i s are being i n t e r f a c e d d i r e c t l y t o l a r g e f i l e s . I n t e r e s t i n computer-aided s y n t h e t i c a n a l y s i s , computer-aided s t r u c t u r e e l u c i d a t i o n , and computer-aided process development remains h i g h , but as these complex a p p l i c a t i o n s are s t i l l i n the a c t i v e development stages they have not yet undergone f u l l - s c a l e i n t e g r a t i o n i n t o e x i s t i n g i n f o r m a t i o n networks. Summary This chapter has o u t l i n e d the nature of the drug development process and has described m e d i c i n a l chemical i n f o r m a t i o n r e t r i e v a l i n terms of a network of d r u g - r e l a t e d i n f o r m a t i o n c a t e g o r i e s . A l l of the systems described i n t h i s volume can be viewed i n terms of t h i s o r g a n i z a t i o n . Some of the systems, notably those of the major pharmaceutical companies and some of the l a r g e r government programs, encompass a l a r g e f r a c t i o n of the drug development funct i o n s and data types. Other systems may i n c l u d e only a s i n g l e f u n c t i o n and r e l a t i v e l y few data types, yet even these s m a l l e r (or l e s s i n t e g r a t e d ) systems feed i n t o and are p a r t of the t o t a l med i c i n a l chemical i n f o r m a t i o n network. This i n t r o d u c t o r y chapter has provided only an overview of the f i e l d and a framework f o r viewing the s p e c i f i c c a p a b i l i t i e s that e x i s t . The d e t a i l s and exact mechanisms are provided i n the papers t h a t f o l l o w and i n the references c i t e d t h e r e i n . RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2

The

PRODBIB

D a t a Base: R e t r i e v a l of P r o d u c t

I n f o r m a t i o n f r o m the P u b l i s h e d Literature

BARBARA C. FREEDMAN Product Information Section, Technical Information Department, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709 The L i b r a r y at Burrough charged w i t h the responsibility retrieving published scientific and medical literature (hereafter r e f e r r e d to as "product papers") about Company products. The references c o l l e c t e d have been used in two ways: (1) to produce b i b l i o g r a p h i e s to accompany I n v e s t i g a t i o n a l New Drug a p p l i c a t i o n s , New Drug A p p l i c a t i o n s , and Annual Reports to the Food and Drug A d m i n i s t r a t i o n ; and (2) to support the Research, Development, M e d i c a l , and Marketing D i v i s i o n s in their ongoing work w i t h Company products. Until 1972 this responsibility was discharged using entirely manual methods. Three files e x i s t e d : (1) a card file, organized by product and, w i t h i n product, by author; (2) copies of b i b l i o g r a p h i e s prepared from these cards s i n c e 1966; and (3) r e p r i n t s of articles published s i n c e 1970. About 25,000 references had been c o l l e c t e d and the files were growing at the r a t e of approximately 5000 per y e a r . Searching these manual files became i n c r e a s i n g l y difficult, as d i d the production of annual b i b l i o g r a p h i e s . In 1972 we s e l e c t e d INQUIRE (Infodata Systems Inc., Falls Church, Virginia) as an appropriate software package to handle a data base of our own d e s i g n , i n t o which we could enter and retrieve b i b l i o g r a p h i c i n f o r m a t i o n , subject i n d e x i n g , and data e x t r a c t e d from the product papers. We c a l l the data base PRODBIB, f o r "product b i b l i o g r a p h y . " Our s e l e c t i o n of INQUIRE was based on the s u c c e s s f u l experience o f other pharmaceutical firms (1). Hardware. From November 1972 to November 1975 we ran our INQUIRE data bases at T r i a n g l e U n i v e r s i t i e s Computation Center, a l a r g e , university-owned computation c e n t e r . In November 1975 we moved INQUIRE operations to our own Computer S e r v i c e s D i v i s i o n , where we have an IBM 370/148, and run INQUIRE under 0S/VS1, i n batch mode. 0-8412-0465-9/78/47-084-010$05.00 © 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2.

FREEDMAN

PRODBIB

Data

Base

11

INQUIRE f a c i l i t i e s . We are c u r r e n t l y using V e r s i o n 9.1, w i t h blocked f i l e s and the m u l t i - d a t a base o p t i o n . O r g a n i z a t i o n of the PRODBIB f i l e . An item i n the PRODBIB f i l e c o n s i s t s o f the b i b l i o g r a p h i c data and indexing terms f o r one product paper. I f two o r more products are mentioned i n one paper, however, we create one item f o r each product. I d e n t i c a l b i b l i o g r a p h i c i n f o r m a t i o n i s entered f o r each, w i t h indexing terms appropriate f o r each product. Items are s t r u c t u r e d according to the f i e l d s d e f i n i t i o n t a b l e (Figure 1). The only r e q u i r e d f i e l d i n the data base i s REPORT, a r e p o r t code and accession number assigned to each paper. For papers which mention more than one product, a DOCPT (a s i n g l e a l p h a b e t i c c h a r a c t e r ) i s assigned. Consequently, REPORT uniquely i d e n t i f i e s the product paper; REPORT and DOCPT uniquely i d e n t i f y a PRODBIB item The f i e l d s PATIEN graphic i n f o r m a t i o n , a quick c a t e g o r i z a t i o n of each paper, and the number of p a t i e n t s i n v o l v e d i n each study. The DRUG f i e l d contains the N a t i o n a l Drug Code number, B.W. Co. compound number, and B.W. Co. tradename f o r the product being indexed. We use the tradename i n the DRUG f i e l d only and generic names i n the remaining f i e l d s . I n t h i s way we can d i s t i n g u i s h i n searching between the product as the subject o f an item and the product used together w i t h or compared to another product. The remaining f i e l d s are used f o r subject i n d e x i n g . For almost a l l of these we use terms s e l e c t e d from MALIMET, the thesaurus of the Excerpta Medica Foundation (2). MALIMET i s a broad and deep l i s t of terms, w i t h f a i r l y good c o n t r o l and a c e r t a i n amount o f s t r u c t u r e . ( I t i s not, however, h i e r a r c h i c a l . ) We have used about 8000 unique terms from MALIMET. Figure 2 shows the content of a t y p i c a l PRODBIB item. Indexing p o l i c y . I t i s our p o l i c y to index only that i n f o r m a t i o n i n a paper r e l e v a n t to our product. We do not index the whole content of a paper, as MEDLARS would, but r a t h e r the narrower range of i n f o r m a t i o n about our product. The primary advantage of t h i s approach i s that we can e l i m i n a t e many f a l s e drops that occur whem we search the " g l o b a l " data bases. Keywords are posted against f i e l d names i n such a way as to create a keyword-in-context s i t u a t i o n , i . e . , a keyword can l a t e r be searched i n terms of the f i e l d i n which i t was entered. For example, the keyword RASH can be used as an i n d i c a t i o n f o r one product, an adverse r e a c t i o n to another product, and a c o n t r a i n d i c a t i o n f o r a t h i r d product. In s e a r c h i n g , the keyword can be used alone or as a f i e l d value c o n d i t i o n of a p a r t i c u l a r f i e l d .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

12 OISPLAY

F I tLDS.

FIELD NAME

KEY

TYPE

STORED LENGTH

STRUC

- PRINT FORM LEN

RPTS

NOTES

UAIAuASc « PROJBIB · REPORT SJUkCE UUCYR JOCNU DUCPT PAT1ENI S Pub γ κ INPUT LONDON INDEXER DRUo OKUGNU JRUGLBLk DRUGPROD JRUGPKG CuMPUuNJ CMP i) NO CMPObRC CMPYK CMPBATCH PRODNAML AUTHùk

PFX PFX PFX

PFX

PFX

PFX

CHR LHR ChR CHR CHR INT CHR i NT CHR CHR CHR CHR CHR CHR CHR CHR

12 4

2 4

1 4

2 6

6 3 38 9

3 * 2 9

CHR

CHR CHR

1 1TL6

CHR

V

CITATΙυΝ L ANGUAGL LULAIIUN CAT E G U R Y TYPE ΙΝυΙοΔΤΝ EFFLC1 LGNCuM CUMPAKE cxpsutij EXPTYP 1 EXP Τ Y P 2 ΕΧΡΝι, tXPStlX I N V 1 Iku PRtPN PREPSKL FORMULA FUkM kAT I C OkUoL CONCl 0RUG2 CUiMC^ DOSAbE DUSfc ROUTE ADVERSE ADVREAC ADVNUM CUNTRINU SENSURG RESISUKG SUBJECTS EFF ICACY NOTES KEYS ITEMNU SFIXEO ALLKEYS

CHR CHR

V

CHR PFX PFX

CHR CHR

SMP

CHR

SVP SMP

LHK

SMP

CHR

2 2 20 24 280 168 15 60 12 9

CHR

<*0 40 40 40 45

SMP

CHR

20

SMP

LHR CHR CHR CHK

20 4

SMP SMP

Pi- X

PFX SMP SMP SMP SMP SMP

CHR

1

CHR

5J 30

CHR

20

CHK

62 12 10

CHR

CHR CHR CHR L HR ChR CHR CHR CHR CHR CHR I.MT CHR CHR CHR CHR CHR CHR BLT BLT CHR BLT

Figure 1.

NB ΝΘ NB NB NB ( NB I NB NB NB NB NB NB NB

V 5 V 5 V 5 V 10 SCALAR SCALAR SCALAR SCALAR V 5 V 2 V 10 V 5 V 5 V 5 V 5 V 5 V 5 V 5 V 5 V 5

NB NB NB NB Β Β NB NB NB NB Β Β Β Β ΝΒ •Ν Β ΝΒ ΝΘ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ ΝΒ Νβ

12 PUS 2 POS 4 POS ι 4

1 TO 6 TU 9 TO

4(REPORT 7(REPORT 12(REP0RT

) 1 )

4

2 6 6 3 38

9 POS 3 PUS 4 POS 2 POS

1 TO 1 TO 4 8

TO TO

9(DRUG 3(DRUG 7(URUG 9(DRUG

) ) ) )

16(DRUG 18(DRUG 38(DRUG

)

2 0 ( E X P SJBJ 40(EXPSUBJ 44(EXPSUBJ 4 5 ( E X P SJBJ

) ) ) i

30(1NVITRO 50(INVITRO

) )

12(FORMULA 22(FORMULA 32(FURMULA 42(FORMULA 52(FORMULA 62(FORMULA

) )

40(DOSAGE 44(DOSAGE

) 1

40ÎA0VERSE 43(ADVERSE

) )

I

CHK

PFA

BASE SUdF SUBF SUBF SUBF

SCALAR SCALAR SCALAR SCALAR SCALAR SCALAR SCALAR SCALAR SCALAR SCALAR V 5 V 5 V 5 V 5 V 5

4

CHR CHK SMP PFX

BASE SUÙF SUBF SUBF

10 10 10 10 44 40

4 43 40

Λ

V

BASE SUBF SUBF SUBF SUBF BASt SUBF SUBF BASE SUBF SUBF SUBF SUBF SUoF SUBF BASE SUBF SJBF BASE SUBF SUdF

V V V V V

5 5 5 5 5

V V

5 5

V V V V V V V

5 5 5 5

V

5

10 10 10 5

2 52 630

V V 20 V 20 V 20 SCALAR SCALAR

40 8 109

SCALAR SCALAR

40 40 40 40

V

SUBF SUBF SUBF

40

I

Β Β Β Β β Β St ΝΒ ΝΒ St

2 PUS 2 PUS 20 24

POS

15 17 19

TO TO TO

) )

280 168 15 60 12

9 40 40 40 40 45 20

PUS

1 TU

PUS

21

TO

POS 1 POS 5 0 30 POS 2 0 POS 62 12 P U S 10 P U S 10 POS 10 POS 10 POS 10 POS

41 45

TO TO

1 31

TO

20 4

44 40

1 TU 13

TU

23 33

TO TU

43

TO

53

TO

POS POS

41

POS 3 PUS

41

4 43 40

TO

1 TO TO

1 TO TU

40 40 40 40 252

63 0 40 8

109 40

Fields definition table for the PRODBIB

data hase

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

)

) ) )

2.

FREEDMAN

SFIXtJ DRUb

PRODBIB

Data

13

Base

(Lbu/77/i399A3J2877ulJi7o ôoLOo^Z SEPTRA iKiMtTHÙPKIM SULFAMETHOXAZOLE STAMEY TA CJNOY A MlHAkA G P k U P H Y L A C T l C E F F I C A C Y OF Ν l T KOFURANT ϋ IM MACKUCR Y S T AL S TRIItTHûPRlM-^ULFAMtTHUXAZJLE IN URINARY INFECTIONS. B I O L O G I C EF F t c TS ON THE V A G I N A L AND R E C T A L F L O R A

AUTHUK

Τ I T Le

CITATION CATEGORY TYPE Ι"Νϋ ICAT Ν Ε F F t. C Γ CONCUR COMPARE EXPSU6J INVITKU FCK.IULA AOVERSE C u M κ ΙΝϋ SENSukG KcS ί SUKL» SUdJEC T S

Ν ENGL J ΝΕΟ 2 9 6 ( 1 4 ) : CL Î N I L - A L PHARMACOLOGY

760-783

JKINAKY I K A C Ï INFtCTIUN K t C U K K E N T J Κ I Ν A k Y TRACT

APR

7,

1977

PkCPHYLAXlo INFECTION

v,LNl KALf.PT IVL A^LNl INTRAOT t K I N r . C b ^ I K A C E P T 1 VE u E V i C E i\i TK Ji- u k ^ N T o l N M AC κ UCk Y S T AL 1 M «ItTHUPKi.M HUMAN AÛJL Γ

002<jF

lAdLcT 4 0 M G T .MP

C K AL

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M G SMX/ϋΑΥ

ο V.uNTHo

I N T E S T I N E FLORA FECES MICKCFLUKA V A G I N A β A C Τ Ε k1 A L F L O k A CUNTRuLLEU C L i M C A L TRIAL HY S T E R E C Γ0ΜΥ JkUG k E S l S T A N C c LSChERICHlA CULl PROTEUS M I R A B I L I S KLEbSlLLLA PSEUOUMUNAS cNT EROCUCCUb LOW J U S E L J N G TE kM T H E H M P Y H FACTÛK

EFFICACY NOTES

Figure 2.

Content of a sample PRODBIB

item

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

A NO

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

AUTHOR=HlSS J AuTHOR=HlTCHLOLK Ck AUThuK=hiTCHCJCk M A U i h C k = H l I C H 1 N G S CH AUThUH = H I T C h l i J o S G AUIHUk = H I T C M N G S o h A U T h u K = r t I T C h l N b S GM A U T H U k = H I T T riA AUTnGR=HlTZENbEkoER G AUTHÛR=HITZENdERGFR H AUTHOR=HlTZIG * Η

Figure 3.

1 i>

Ιβ

A portion of the PRODBIB

author index, part of the

system-generated

DISPLAY

*rpi.RT=TL»JJ//6/129i

k Γ Ρ J * Τ = TL b J / 7 o / L 3 4 J .

KEY W U k u J i S P L A Y F ^ k J A I A J A S L REPUkT=Ti_tiJ/7o/i2^i REPUhT = T L b J / 7 b / l < ? 9 2 REPUkT^TLuG/70/1293 RfcPOR T = l L b U / 7 6 / 1 2 ^ REPUKT=TLB0/^6/i2S5 KEPORT^TLdD/76/129o REPOk 1 = T L b u / 7 o / U i l REPUK r = T L H j / 7 6 / 1 2 } d REP0RT = TLB0/7t>/1299 RfcPORT^iLBu/7o/i300

PKuGolc

<

Figure 4.

A portion of the PRODBIB

report code index, part

of the keyword list (with frequency counts)

DISPLAY

L A N G U A G t = H F riRtW L A N o U A G b = P O L I S H .

KEYWORD D I S P L A Y F L R U A Î A b A S t LANGUAGE=HEBRF* LANGUAuE=FUNoA*IAN L A N G U A G L = I T A L I AN LANoUAGE=JAPANESE LANGUAGl>KGREAN LANGUAGt=Nûk*EbiAN

PROCbld

L A N G U A G E - P O L ISH

Figure

5.

Language

4 42 377 39 3 lu 06

designations on the keyword frequency

list (with

counts)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2.

FREEDMAN

PRODBIB

DISPLAY

Data

15

Base

C ARBArtAZ t P I N t

C Α Κ ό I NOMA «

K E Y A U K J D I S P L A Y E O :) Λ Τ Α ο Λ S 4; C A R b A M A Z L PINT. CAKUArf/ULPINfc DERIVATIVE CAkoAhYLPFUSPHATE 6 Y N 1 H ETASE C A k b A N I L I c AC I ) U t k l V A T l V c CAkb AZULt. C J I N L N L C ARbAZ Y L U C I N L N E CARbENiCILLIN C A R b E N I C I L L IN J i i C D l U r t SALT C A R B E N I C I L L IN 1 N D A N Y L SciDIUM CARtfENUXALGNE

PrvuiJJÎH

1

Figure 6.

4 22

MALIMET

FINO SEPTRA AND CATEGORY=CLIΝICAL AND · R E C U R R E N T URINARY TRACT tBIBLIOl, HEADER 'SEPTRA AND RECURRENT URINARY TRACT I N F E C T I O N * .

SEPTRA ANO RECURRENT

URINARY

TRACT

INFECTION*,

INFECTION

ΚONIΝ CM TLBD/75/2958 URINARY TRACT INFECTIONS. FLOW CHARTS (ALGORITHMS) FOR DETECTION AND TREATMENT JAMA 2 3 3 ( 5 ) : 458-462 AUG 4 , 1975 MENT ION LEVY Sb TLbD/77/1694 FECAL FLORA IN RECURRENT URINARY TRACT INFECTION Ν ENGL J MED 2 9 6 ( 1 4 ) : 813-814 APR 7, 1977

LINES D TLBD/77/U94 CHILDHOOD URINARY CANDIDIASIS SUCCESSFULLY TREATED WITH 5-FLUOROCYTOSINE AUST PEDIATR J 1 2 ( 1 ) : 4 9 - 5 2 , 1976

MAGANTO Ε TLbD/75/3462 PEREZ COUTINO A TREATMENT OF REFRACTORY URINARY INFECTIONS WITH ARCH ESP UROL 2 4 ( 4 ) : 3 6 9 - 3 7 8 , 1971 SPANISH

Figure

7.

PRODBIB

TRIMETHOPRIM-SULFAMETHOXAZOLE

search using keywords (search specification followed by search results)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

16

PINO

Z Y L U P R I M AND C A I l G O k Y = C L I N 1 C A L AND 1 N 0 1 C A Ï N &BIQLIG1, HEADER « Z Y L u P k l M T k c A l M c N T Or G O U T .

IS

GUUT,

1

ZYLOPkiM

ΤηεΑΓΊίΝΓ

„UUT

uh

G R E E N E ML T L B O / 74/2.439 GLUECK C J FUJIMuiU *Y ShEGMILLE k JE d c N I G N S Y M M E T k I C L I P 0 M A T U 5 I S (L A J Ν υ IS - ί3 L Ν ;> A U D Ε W11 H cOUT AND H Y P E R L I P O P R O T E I N E M I A AM J MED 4 8 ( 2 ) : 2 3 9 - 2 4 6 F E B 1970

G R E E N c ML C L I N I C A L FEATURES THE

X-LINK-D

ARCH

INTERN

Of

PATIENTS

wITh

1LrtU/74/134} Τ HE«PAk1 I A L "

KNAPP

DEFICIENCY

OF

U R l C A c l D U R I A ENZYME ftJ

1^012):

193-1^8

AuG L 9 7 2

GRE1L1NG H T L b 0 / 7 H / J> 3 71 P R E S E N T P k O b L t h S OF G u U T . C L I N I C A L b I CCHc M I :> I RY THfcRAPI EwCChE 2 2 ( 2 ) : 77-8*, 1972 TRANSLATION GERMAN GUNTHtk

AU LNUL i POMATOS IS)

k

UF

oJUl

lL:W7o/3l94

Ε

CLINICAL

FINDINGS

ME T A B O L I C

EFFECTS

AND THERAPY OF

OF

oOUT

SULFINPYRAZONE

WITH S P E C I A L

(ANTUkAN)

REFERENCE

10

THE

AND A L L OPURINOL

(ZYL0R1C) WlEN

K L I N WOCHENSCHR GERMAN

Figure 8.

PRODBIB

Hi:

817-320

NOV 7 ,

1969

search using field value conditions (search specification followed by search results)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2.

FREEDMAN

PRODBIB

Data

CLINICAL

Base

USES

17

OF A L K E R A N

INOICATIUN

ITEMS

OSTEOSARCOMA OVARY A O E N O C A R C I ΝCMA OVARY CANCER OVARY CANCER M E T A S T A S I S OVARY CARCINOMA OVARY C Y S T A u c N U C A R C I NOMA OVARY TERATOMA OVARY TUMOR PANCREAS AUENOCARCINGMA PANCREAS CANCER

CLINICAL

25 2 36 I 38 2 1 2 I I

USES

OF A L K E R A N

M U L T I P L E MYELOMA L A T O S OL V A L E N T I N E AM TREATMENT

VIRGINIA

OF

JLÙ0/73/0369 HYPEKCALCE'-I

M F13

J 69(3):

1A * i i h

52-6*

F'.JROStMloh

MARCH

AIML>

COk I I C u o I L R O I O S

197;

M U L T I P L E MYELuMA LAW IP TLbW 7θ/ϋο09 PLOVNICK H J ùEOUOw OG MOL Τ I PL Ε M Y E L O M A , S I J i _ R u b L A S I IC Α Ν Γ . Μ Ι Α Α Ν ύ Α ν , υ Τ Ε Ν E N u L J MEO 2 9 * ( 3 ) : l o ^ JA.N 1 5 , 1 9 / 6 L E I Τ Εκ

LEUKEMIA

M U L T I P L E MYELOMA LAw M t P T L < W 7o/106i> F A M I L I A L OCCURRENCE OF M U L T I P L E MYcLOMA SOUTH M c J J 6 9 ( 1 ) : 4 6 - t . J J A N 1 9 7 6

M U L T I P L E MYELOMA LE C H E V A L L l E k PL T k t Α ί MENT OF M Y t L L M A . SEM HOP P A k i S 4 / : 2 * 9 - 2 3 1 FRENCH

Figure 9.

PRODBIB

TL8U//2/G226 J A N 20,1971.

search listing réfrénées

wtih a table of contents

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

18 ADVERSE

REACTIONS

TO S E P T R A

FOLIC ACID DEFICIENCY BUSHbY SRM I f< I M E T h ù P r I Μ A N D SUE P H U I N A M I D E S : S

FOLIC

At- R

MED J

iVCI'J

CLARK

44(SUPPL):

3 - 1 0 AUu

TLbD/74/103ô LAoJRATJRY STJOHS 15,

197J

DEFICIENCY F

TL3D/76/4108

i M u G S MI\J V I T A M I N DEFICIENCY A O V E K S L DkJO FFAC1 bULL 5 7 : 1 9 o - 1 9 9 ,

FOLIC

ACI J

C L L MAN HERBERT

JLFICIENCY Ν

TL30/76/419 7

V

C u I k I MU X A Z J L Ε

LANLcï

FOLIC ACIu DAVIS JALKSLN

2
A N J Fl.LATE

96

METADLLISM

DEFICIENCY ftt

Τ L JJ/ 7 3 / 0 7 5 3

J-1

ί Κ 1 Mt I HuP Κ I M / ^ J L P H M M h Τ ' 10A A Z u L f:

PAT HuLUGY

Figure 10.

197o

5 ( 1 ) : 23-29

PRODBIB

ANJ

FOLATL

MCTAUULISM

J A N 1973

search listing adverse reactions and bibliographic reference

TREATMENT OF POLYCYTHEMIA

VERA WITH B.W. C O . PRODUCTS

LEUKERAN WESTIN J TLBD/77/2527 CHROMOSOME ABNORMALITIES AFTER CHLORAMBUCIL THERAPY OF POLYCYTHAEMIA VERA SCAND J HAEMATOL 1 7 ( 3 ) : 1 9 7 - 2 Û 4 SEP 1976 LEUKERAN WALL Ε RST Ε IN RO TLBD/77/3174 POLYCYTHEMIA VERA-tfHU NEEDS THERAPY? CONSULTANT 1 7 ( 4 ) : 14B-156 APR 1977 MYLERAN KAHN SB TLBD/73/0368 BRUDSKY I THERAPY OF MYELOPROLIFERATIVE OISORJERS CANCER CHEMOTHER II ED BY I BRUDSKY AND SB KAHN NEW YORK LONDON GRUNE AND STRATTON 1972 PP 347-359 REVIEW MYLERAN WASSERMAN LR TLBD/73/0273 THE MANAGEMENT OF PCLYTHAEMIA VERA BR J HAEMATUL 2 1 ( 4 ) : 371-376 OCT 1971 MENT IuN REVIEW

Figure 11.

PRODBIB

search listing various products used to treat one disease

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2.

FREEDMAN

PRODBIB Data Base

19

Keyword l i s t . The keyword l i s t which i s generated as a r e s u l t of our s p e c i f i c a t i o n s i n the f i e l d s d e f i n i t i o n t a b l e contains an author index and a report code index (Figures 3 and 4 ) . In a d d i t i o n , LANGUAGE, TYPE, CATEGORY, COMPOUND, and ROUTE are p r e f i x e d keywords (Figure 5 ) . A l l other f i e l d s w i t h MALIMET terms are keyed (Figure 6 ) . Data e n t r y . We enter b i b l i o g r a p h i c data and indexing terms onto p r e p r i n t e d forms. The data i s then keypunched, e d i t e d from d i s k using the IBM CMS e d i t o r , put on tape, and the INQUIRE updates done from tape. T y p i c a l search products. A m a j o r i t y of the searches done on the PRODBIB f i l e combine a drug name and one or more keywords (Figure 7 ) . Less f r e q u e n t l y , a drug name i s combined w i t h a f i e l d value c o n d i t i o n t y p i c a l searches, we ca by i n d i c a t i o n or adverse r e a c t i o n . These can be e i t h e r l i s t s of the b i b l i o g r a p h i c references themselves or l i s t s of the keywords w i t h a count of the number of items i n which they have been used ( F i g u r e 9 ) . O c c a s i o n a l l y we produce l i s t s of adverse r e a c t i o n s o c c u r r i n g during treatment of p a r t i c u l a r diseases (Figure 10). Another type of search r e s u l t s i n l i s t i n g s of references by product f o r the treatment of c e r t a i n diseases (Figure 11). U t i l i z a t i o n of the data base. We run about 50 queries per month to answer questions r e c e i v e d i n our reference a c t i v i t i e s . We f i n d INQUIRE to be an extremely f l e x i b l e t o o l f o r the b u i l d i n g of a b i b l i o g r a p h i c data base, and have been very pleased by i t s a b i l i t y to respond to our needs.

Literature cited. 1 Bennett, R . E . and S.J. F r y c k i - I n t e r n a l processing of e x t e r n a l reference s e r v i c e s . J . Chem. Doc. 11(2): 76-83, May 1971. 2 Blanken, R . R . and B . T . Stern - Planning and design of o n - l i n e systems f o r the u l t i m a t e user of biomedical i n f o r m a t i o n . I n f . P r o c . Man. 11(8-12): 207-227, 1975. RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3

Automation

of T e s t - D a t a

Transmission

from Producer

to

C o m p u t e r Master File

H E L E N F. GINSBERG, DAVID J. JAMES, and CHRIS R. MONDELLO Abbott Laboratories, North Chicago, IL 60064

Input t o the Abbot System (ABCD) (1,2) a p r o p r i e t a r a decade, was not efficient by current data h a n d l i n g standards. Until recently test r e s u l t s on i n t e r n a l compounds were t r a n s c r i b e d onto a p p r o p r i a t e code sheets, keypunched and verified, then sent t o the corporate computer center f o r entry into the master data base. Not only were these m u l t i p l e operations time consuming, but wit h each r e c o r d i n g o f the data there was another chance f o r human e r r o r . The p o t e n t i a l f o r human e r r o r can be decreased by e l i m i n a t i n g , wherever a p p r o p r i a t e , keypunching o f large volumes of data per experiment or transcription of results from computer statistical calculations by having the experimenter enter original observations directly onto a computer t e r m i n a l . All f u r t h e r p r o c e s s i n g o f the raw data would be c o n t r o l l e d by computer programs. Humans would i n t e r v e n e only when r e q u i r e d for v i s u a l e v a l u a t i o n o f the i n f o r m a t i o n or approval o f outputted results. This r e v i s i o n in data h a n d l i n g procedures i s c u r r e n t l y underway. Agricultural Research Manual Data E n t r y . The a g r i c u l t u r a l research program was one area i n which the r e c o r d i n g , keypunching and p r o c e s s i n g o f the t e s t r e s u l t s was becoming very c o s t l y . A d d i t i o n a l l y , as i l l u s t r a t e d i n F i g u r e 1, there was considerable s h i p p i n g o f paper copy from one p h y s i c a l l o c a t i o n t o another. A f t e r the data were recorded on the code sheet, a s m a l l p o r t i o n o f which i s shown i n F i g u r e 2 , a c t i v i t y r a t i n g s were added and the sheets copied f o r s e c u r i t y . M a i l s e r v i c e between A b b o t t ' s Research Farm and our North Chicago f a c i l i t y was slow, sometimes r e s u l t i n g i n a delay of s e v e r a l days before the t e s t r e s u l t s were r e c e i v e d f o r keypunching. Only a f t e r the v e r i f i e d data cards were read i n t o t h e R&D DEC-System 10 f i l e was f u r t h e r processing r a p i d . 0-8412-0465-9/78/47-084-020$05.00 © 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG ET AL.

Automation

of Test-Data

Transmission

21

DATA MANUALLY , i RECORDED /

ACTIVITY RATINGS ADDED

COPIED SHEETS RETAINED AS BACK UP

DATA SHEETS COPIED

ORIGINAL D A T A SHEETS MAILED TO NC

DATA

r

DATA CARDS VERIFIED

DATACARDS READ

DATA CARDS DESTROYED

DATASHEETS RETURNED TO FARM

w

D A T A SHEETS R E T A I N E D AS REFERENCE

5 D A T A ON DEC-10 DISK FOR UPDATE

IT

Figure 1.

Data flow in manual data entry system

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

22

CARD 1

A-NUMBER

SEQ. NO.

1-6

74-76

20-27

VELVE LEAF

36-43

28-35

WEED

44-51

DOCK

WEED

PORTION O F HERBICIDE C O D E SHEET

10C4H

1

0

IOC4H7Y

1

0

IOG5E/3B

1

0

WRITTEN

c c G

4

H

4

H

*

5

Ε

Β

/

PUNCHED

RESPONSE FOR O N E P L A N T SPECIES

Figure 2.

Detail of herbicide code sheet

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG E T A L .

Automation

of Test-Data

Transmission

23

An e n t i r e page o f typed i n s t r u c t i o n s f o r t h e keypunch operators accompanied t h e completed forms which had been designed o r i g i n a l l y f o r ease o f f i e l d r e c o r d i n g o f data i n h e r b i c i d e and growth r e g u l a t o r t e s t s . A t t h a t time the data were not being entered i n t o a computer system. Figure 2 i l l u s t r a t e s the d e t a i l t h a t could be recorded f o r one or more o f the p l a n t s p e c i e s s t u d i e d . I n c l u s i v e card columns f o r t h e s p e c i f i c f i e l d s were p r e p r i n t e d on the code forms. These card columns were not always i n sequence, as can be seen i n t h e figure. A d d i t i o n a l l y , f o r a c t i v e compounds there might be more observations recorded on the sheet than could be accommodated by the e i g h t columns allowed f o r each p l a n t . An a s t e r i s k i n the l a s t column o f the f i e l d , shown on t h e second l i n e of the "Response f o r one P l a n t S p e c i e s " would denote " A d d i t i o n a l Information A v a i l a b l e on the O r i g i n a l Record". The observer would record the respons keypunch operator was the i n f o r m a t i o n on the cards. Obviously keypunching would be slow. I n 1975 charges f o r keypunching and v e r i f i c a t i o n f o r two of the t e s t s recorded on these forms averaged $1.05 per compound. Automated Data Entry. I n mid-1975 an e f f o r t t o e l i m i n a t e or reduce e x i s t i n g manual data r e c o r d i n g systems i n the ongoing a g r i c u l t u r a l research program was begun. Although the e f f o r t was p r i m a r i l y d i r e c t e d a t reducing hand coding and t r a n s c r i p t i o n of chemical h e r b i c i d e and p l a n t growth r e g u l a t i o n s c r e e n i n g r e s u l t s , a d d i t i o n a l a p p l i c a t i o n s i n f i e l d p l o t research were also studied. System Design C r i t e r i a . The c r i t e r i a used t o evaluate and design the automated data c o l l e c t i o n system were: 1. Hardware P o r t a b i l i t y - A g r i c u l t u r a l research data i s generated i n a v a r i e t y of l o c a t i o n s . Screening systems may operate i n t h e high humidity and temperature of a greenhouse as w e l l as i n the c l e a n , c l i m a t e - c o n t r o l l e d l a b o r a t o r y . F i e l d p l o t research may be l o c a t e d miles from the nearest b u i l d i n g , and data c o l l e c t i o n must be done under a l l k i n d s of weather c o n d i t i o n s . To operate under these conditions, the c o l l e c t i o n hardware must be self-powered, f a i r l y t o l e r a n t o f i t s environment and o f a size and weight that a l l o w s easy c a r r y i n g . Remote t r a n s m i s s i o n o f the c o l l e c t e d data t o a computer mainframe over normal telephone l i n e s a l s o i s r e q u i r e d . 2. P o t e n t i a l B e n e f i t s - A s u b s t a n t i a l number o f e x i s t i n g manual data systems should be replaced. There should be s a v i n g of people hours and improved accuracy.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

24

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

3. User Acceptance - T r a n s i t i o n t o a new system should be accomplished with minimal d i s r u p t i o n i n work flow. An automated system t h a t c l o s e l y resembles e x i s t i n g manual r e c o r d i n g schemes w i l l almost always gain quick user acceptance. F a i l u r e t o o b t a i n t h i s approval w i l l destroy any chance of s u c c e s s f u l system implementation. 4. GLP G u i d e l i n e s - The system should conform t o Good Laboratory P r a c t i c e s r u l e s f o r data c o l l e c t i o n and h a n d l i n g Q). 5. Compatability With E x i s t i n g Computer Systems - The c o l l e c t e d data should be acceptable t o e x i s t i n g databases. Minimal or no a d d i t i o n a l equipment or m o d i f i c a t i o n should be r e q u i r e d t o f a c i l i t a t e the t r a n s m i s s i o n of data t o the computer mainframe 6. F l e x i b i l i t y - The system should be adaptable t o the recording of various types of data. Alphanumeric capability i s required. Simple methods for data identification, f o r m a t t i n g and e d i t i n g are necessary* Recording o f any type of data from a s i n g l e numeric entry to annotations and r e s e a r c h e r s ' comments should be acceptable. Varying the k i n d of data c o l l e c t e d should not require any change in the basic collection-transmission-mainframe acceptance system. 7. System Support - Reprogramming of the system should l i m i t e d t o the secondary r e f o r m a t t i n g steps.

be

System C o n f i g u r a t i o n . A two l e v e l software o r g a n i z a t i o n i s used t o a t t a i n maximum f l e x i b i l i t y w h i l e not d i s t u r b i n g the b a s i c data c o l l e c t i o n system. 1. Primary Software - Three l i n k e d system Macros serve the b a s i c procedures of the data c o l l e c t i o n system. f u n c t i o n s of these programs are:

as The

a. Answering the phone l i n e , l o g g i n g the job i n t o the system, and l o g g i n g the job o f f the system a f t e r sensing the end of f i l e c o n d i t i o n . b. Acceptance of data a f t e r a s s i g n i n g a unique s e q u e n t i a l filename t o the t r a n s m i s s i o n and s t o r i n g of the f i l e on disk at a known l o c a t i o n . c. I n t e r p r e t a t i o n of the f i l e e d i t i n g and formatting c h a r a c t e r s as f i n a l preparation f o r t h e i r r e f o r m a t t i n g by higher l e v e l language programs.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG

E T AL.

Automation

of Test-Data

Transmission

25

2. Secondary Software - S e v e r a l r e f o r m a t t i n g programs, w r i t t e n i n COBOL and FORTRAN, are c a l l e d by the user according t o the type of data being processed. The flow of these programs allows the user t o e d i t - i n a d d i t i o n a l data such as a c t i v i t y r a t i n g s , c o r r e c t i o n s and comments. The use of higher l e v e l languages allows these r e f o r m a t t i n g programs to be w r i t t e n by programmers who are not familiar w i t h the o v e r a l l system. The only programming requirements are knowledge of the data format as i t emerges from t h e primary software and o f the f i n a l format needed by the user. 3. Hardware - The p o r t a b l e data entry t e r m i n a l chosen f o r the system was an MSI Data Corporation Source 2002 (4.). This battery powered device has a t y p e w r i t e r s t y l e keyboard t h a t can generat characters -, + a d d i t i o n a l user requested c h a r a c t e r s . The u n i t records data on a d i g i t a l grade c a s s e t t e tape that has a c a p a c i t y of 30,000 characters per s i d e . The standard data r e c o r d i n g code i s ASCII, and i t i s w r i t t e n i n a s e l f c l o c k i n g mode. Automatic d e t e c t i o n of double k e y i n g i s standard and options such as p a r i t y checking, f i e l d length checking, and check d i g i t s are a v a i l a b l e . An o p t i o n a l paper s t r i p p r i n t e r i s a v a i l a b l e f o r use as a backup data r e c o r d i n g device, to s a t i s f y c e r t a i n GLP requirements f o r t i m e l y hard copy, and as an i n d i c a t o r t o the operator f o r t r a c k i n g what i s a c t u a l l y being entered i n t o the machine. T o t a l weight of the u n i t when equipped w i t h the o p t i o n a l p r i n t e r i s 7 pounds. The transmission of data i s character synchronous at 1200 baud. The t r a n s m i s s i o n c h a r a c t e r i s t i c s are compatable w i t h AT&T 1001Β Data Couplers and 202S Datasets, and voice grade l i n e s are acceptable. The computer mainframe used t o support t h e data c o l l e c t i o n system i s a DEC-System 10 which operates as a time-sharing s e r v i c e t o the corporate research d i v i s i o n s o f Abbott Laboratories. Communications between t h e data c o l l e c t i o n t e r m i n a l and the mainframe are handled through a dedicated d i a l - u p access port equipped w i t h an AT&T 202S Dataset. A minimum amount of m o d i f i c a t i o n of the TOPS-10 o p e r a t i n g system was r e q u i r e d t o completely implement r e l i a b l e transmissions and acceptance of the data streams coming from the MSI equipment t o the DEC-System 10. System Operation. A c t u a l operation of the system i s very s t r a i g h t f o r w a r d and c l o s e l y resembles the p e n c i l and paper method i t replaces (See Figure 3). A l l data are recorded on the c a s s e t t e and a f t e r v e r i f i c a t i o n sent v i a telephone l i n e s to the DEC-10 computer. As the data are recorded, the operator simply enters the same codes, values, or whatever e l s e was used i n the

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

26

Figure 3.

O F MEDICINAL

CHEMICAL

INFORMATION

Data flow in automated data entry system

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG E T A L .

Automation

of Test-Data

Transmission

27

manual system. The only r e a l d i f f e r e n c e i s the use of s p e c i a l c h a r a c t e r s t o take t h e place of p r i n t e d l i n e s to i d e n t i f y separate e n t r i e s and l i n i n g - o u t t o make c o r r e c t i o n s . The operator r e t a i n s a l l t h e f l e x i b i l i t y that the manual system allowed regarding comments, s k i p p i n g e n t r i e s , or r e c o r d i n g complete records i n any order. The only r e a l r e s t r i c t i o n imposed upon the r e c o r d i n g process i s that each complete record must contain an exact number of entry f i e l d s whether there i s a value i n the f i e l d o r not. This r e s t r i c t i o n i s , again, no more than i s found i n t h e manual system, but i t can cause some problems i f the operator does not have a c l e a r mental p i c t u r e of the analogies between the automated system and the manual one. Figure 4 i l l u s t r a t e s the various changes a s e t o f data undergoes i n being converted from the o r i g i n a l recorded observations u n t i l they are ready t o be submitted t o the master data base. The characte actual representation o the i n f o r m a t i o n t h a t i s t r a n s m i t t e d t o the R&D DEC-System 10 f o r f u r t h e r processing. The f i r s t ten characters preceeding the "-" s i g n are f o r t r a n s m i s s i o n s y n c h r o n i z a t i o n . The "-" s i g n i s used t o e d i t them out of the f i l e . Throughout the data entry process the up-arrow i s used t o s i g n a l "end o f r e c o r d . " The "+" i s a f i e l d d e l i m i t e r ; entry of "++" w i l l f o r c e a blank f i e l d i f there i s no t e s t i n t h a t run f o r a p a r t i c u l a r plant species which was i n t h e sequence being studied in concurrent experiments. The " ? " and "-" are used f o r d e l e t i o n , "?" f o r s i n g l e c h a r a c t e r s and "-" f o r an e n t i r e f i e l d . The next f i e l d c o n t a i n i n g "A" and numbers separated by "+" i s a heading r e c o r d w i t h t e s t date and amount o f compound a p p l i e d per acre (test r a t e ) . The l a s t character s t r i n g between the up-arrows i n c l u d e s the number of the compound being tested, second test i d e n t i f i c a t i o n and p l a n t readings f o r the various species being studied. Other i n f o r m a t i o n r e q u i r e d f o r the complete r e c o r d i n g o f t e s t r e s u l t s from t h e f i e l d or greenhouse are entered on the c a s s e t t e i n a s i m i l a r manner. For example, a t w o - d i g i t number i s used t o i d e n t i f y the various plant species that might be s t u d i e d . Only a l i m i t e d number of these would be s t u d i e d at any p a r t i c u l a r time and, thus, would have t o be entered w i t h the observed r e s u l t s f o r t h a t experiment. A "C" record i s used t o post the p l a n t species f o r t h e run or runs on any day; i d e n t i f i c a t i o n numbers are recorded i n t h e same sequence i n which the r e s u l t s w i l l be read and entered. This information i s keyed as "C+" f o l l o w e d by the t w o - d i g i t numbers separated by "+", then t h e end o f record c h a r a c t e r . I f there are no v a r i a t i o n s during the course of one day's readings i n t e s t dates, t e s t r a t e s , method o f a p p l i c a t i o n , or t e s t plant sequence, only one set o f header records i s r e q u i r e d . I f the p l a n t sequence remains constant over a p e r i o d of time, i t need not be re-entered d u r i n g t h a t time i n t e r v a l . Λ

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

28

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG E T A L .

Automation

of Test-Data

Transmission

29

A f t e r the data are t r a n s m i t t e d from the research farm to the R&D DEC-System 10 and the i n s t r u c t i o n s transmitted with the data c a r r i e d out, the e d i t e d records are transmitted back to a t e r m i n a l at the farm and p r i n t e d i n the expanded format as shown under TYPE HAVGRP.CDS. In the t e s t s used f o r t h i s illustration a maximum o f three readings could be recorded for each p l a n t , each reading r e q u i r e s a length of four characters (including blanks). A "++" entered through the MSI would force a 1 2 - p o s i t i o n blank f i e l d i n the a p p r o p r i a t e p o s i t i o n i n the edited record. With t h i s method o f input, simple m o d i f i c a t i o n of entry programs allows the experimenters to record more d e t a i l e d observations than were permitted with the manual data entry procedure. The next stage i n processing o f the t e s t results requires the l i n k i n g of a l l pertinent data for these experiments p r i o r t o f i n a l r e f o r m a t t i n g for The c o l l a t e d records fo the MSI terminal are shown under TYPE SECOND.CDS. Two plant s p e c i e s already i n the s t o r e d "C" f i l e but not included i n t h i s experiment, "19" and "05", appear i n the r e c o r d . These species identifications w i l l be deleted before f i n a l formatting for the corporate master data base. I f there were, i n f a c t , data for plant "19", a s o r t routine would rearrange a l l plant species i n ascending numerical order with the a p p r o p r i a t e information being carried along. This sort routine was included i n the program s e r i e s to s i m p l i f y f i n a l processing of the information i n the corporate data base. A l l the c o r r e c t e d t e s t r e s u l t s are stored i n the DEC-10 i n a compacted form u n t i l just p r i o r t o the update of the master data base. A t that time these data are reformatted as shown under TYPE UPDATE,CDS. Each experiment's r e s u l t s are expanded i n t o three 80 character r e c o r d s , c o n t r o l characters needed for the next series of programs added, and the records shipped t o another f i l e i n the DEC-10. This latter file contains all update data that w i l l be sent t o the corporate IBM 370/158, on which ABCD r e s i d e s , a f t e r a s e r i e s of e d i t s and housekeeping chores have been completed. These same h e r b i c i d e t e s t r e s u l t s are p r i n t e d , as d i s p l a y e d i n Figure 5, on Drug Record Sheets generated from the corporate data f i l e s . Automation of the r e c o r d i n g and processing o f h e r b i c i d e data has cut the cost of p r o c e s s i n g these t e s t r e s u l t s by a factor of four (compared with the keypunching route). A d d i t i o n a l l y i t has: 1.

Increased the accuracy of data

entry,

2. Decreased the time l a g from experiment t o r e c o r d i n g the master data base, 3.

Made

the

experimenter

totally

responsible

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

in

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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NON-MAZARDOUS MATERIAL

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3.

GINSBERG E T A L .

Automation

of Test-Data

31

Transmission

v a l i d a t i o n o f i n f o r m a t i o n before entry i n t o the corporate data base, and 4. Given the researcher a s a t e l l i t e computerized data base.

personal

Since the data f i l e i s i n i t i a l l y c o l l e c t e d i n a machine readable form t h a t has a very general format, individual researchers began t o develop t h e i r own s p e c i a l i z e d data bases with t h i s information. Within a p r o j e c t these s c i e n t i s t s can search t h e i r own f i l e s , prepare t h e i r own customized r e p o r t s on these data and g e n e r a l l y access t h e i r own data from remote t e r m i n a l s . Inasmuch as t h i s same i n f o r m a t i o n has been sent t o the corporate computerized data f i l e s , they a l s o can request searches across p r o j e c t l i n e s t o compare t h e i r data with other t e s t r e s u l t s on compound Although t h i s syste a g r i c u l t u r a l research area, i t i s f l e x i b l e enough t h a t the b a s i c hardware and software have been adopted by other corporate research areas f o r use i n d i f f e r e n t types o f screening systems. Pharmacology Data The concept o f automation of i n f o r m a t i o n t r a n s f e r from t h e o r i g i n a t o r t o the corporate data base a l s o has been a p p l i e d t o pharmacology data, e s p e c i a l l y s i n c e most o f our pharmacology l a b o r a t o r i e s have t e r m i n a l s (hard copy and/or CRT) l i n k e d t o the DEC-System 10 computer. S t a t i s t i c i a n s r o u t i n e l y supply programs f o r t h e a n a l y s i s o f raw data entered e i t h e r manually at a t e r m i n a l o r acquired o n - l i n e d u r i n g the course of an experiment. Output from the s t a t i s t i c a l analyses of these experiments, such as mean, standard d e v i a t i o n , s t a t i s t i c a l s i g n i f i c a n c e , and t h e l i k e , are i n c l u d e d i n p r i n t e d r e p o r t s . I n the past, summary i n f o r m a t i o n f o r these r e s u l t s would have t o be manually t r a n s c r i b e d , then keypunched f o r entry i n t o the master data base. Because o f the e x t r a e f f o r t r e q u i r e d , some t e s t r e s u l t s were not being entered i n t o the corporate data base, but the o r i g i n a l data e n t r i e s were being preserved on backup tapes. With only paper copy r e p o r t s a v a i l a b l e , these experimental r e s u l t s could not be computer searched or r e a d i l y compared w i t h r e s u l t s of other s c r e e n i n g t e s t s . D i u r e t i c Data. One program area i n which data had been recorded on backup tapes but not reported t o the corporate research data base was a r a t d i u r e t i c screen. The o r i g i n a l computer programs, w r i t t e n i n BASIC and used f o r data entry and s t a t i s t i c a l a n a l y s i s , were a l s o on these tapes. Recorded observations f o r each experiment were entered i n t o unique data f i l e s which would have t o be c a l l e d f o r by number from w i t h i n the s t a t i s t i c a l program. The f i r s t l i n e of each of these data

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

32

O F MEDICINAL

CHEMICAL

INFORMATION

f i l e s was a l i t e r a l or header l i n e , an alphanumeric s t r i n g o f v a r i a b l e l e n g t h , with v a r i a b l e amounts of information entered i n any sequence i n the l i n e . The p o s s i b l e i n c o n s i s t e n c y i n header l i n e format i s not c r i t i c a l i f the header i s t o be used only t o i d e n t i f y a p r i n t e d t a b u l a t i o n of s t a t i s t i c a l r e s u l t s s i n c e t h e contents can be i n t e r p r e t e d by the reader. However, i f the contents are t o be used t o access data and r e s u l t s o f analyses f o r f u r t h e r computer processing, s t a n d a r d i z a t i o n i s necessary. There were three major reasons f o r w r i t i n g a s e t o f programs to s t a n d a r d i z e the data r a t h e r than a l t e r the method of data entry. F i r s t , i t was e a s i e r t o w r i t e two mainline programs, one t o handle the data before s t a t i s t i c a l treatment (the s t a t i s t i c a l programs were already w r i t t e n ) , and one t o generate r e p o r t s a f t e r the a n a l y s i s r a t h e r than i n c o r p o r a t i n g a l l t h r e e f u n c t i o n s i n t o one massive program. Secondly, t o enhance the u s e f u l n e s i n c l u d e s e v e r a l years o c u r r e n t i n f o r m a t i o n i n t h e master data base. E n t e r i n g the c u r r e n t data i n a new ( f i x e d ) format would r e q u i r e e i t h e r separate programs t o i n t e r p r e t t h e backlog and current data f i l e s or r e - e n t r y of the header l i n e s f o r a r c h i v a l data. T h i r d l y , a f i x e d format places unnecessary r e s t r i c t i o n s on the user i n that i t does not allow as much f l e x i b i l i t y f o r data entry. The additional computing time required f o r i n t e r p r e t a t i o n of the data i n a v a r i a b l e format was not considered as important as ease of use f o r the end user. To accommodate both current and previous experiments w i t h a s i n g l e program, an automated system t o handle these data was w r i t t e n i n three b a s i c modules (Figure 6 ) . T h e i r f u n c t i o n s were: 1. I n t e r p r e t a t i o n of f i l e headers and grouping of f i l e s by experiment, 2.

S t a t i s t i c a l a n a l y s i s of the data, and

3.

Generation of r e p o r t s based on the analyzed data.

S i n c e the s t a t i s t i c a l programs were already w r i t t e n , module 2 was e s s e n t i a l l y complete, except f o r minor m o d i f i c a t i o n s t o the output of the a n a l y s i s programs t o s i m p l i f y t h e p r o c e s s i n g i n module 3. Hence the f o l l o w i n g d i s c u s s i o n deals mainly w i t h modules 1 and 3. The d i u r e t i c data are entered i n two f i l e s f o r each t e s t compound or s e t of c o n t r o l animals. One f i l e , named DATn.BAS (n = 1-999), contains the u r i n e volume and e l e c t r o l y t e assay data f o r each animal i n the t r e a t e d or c o n t r o l groups (Figure 7). The second f i l e , WGTn.BAS (n = 1-999), contains t h e i n d i v i d u a l animal weights. The f i l e s are given names i n ascending numerical order w i t h the c o n t r o l f i l e r e c e i v i n g t h e lowest

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

GINSBERG E T A L .

Automation

DATA FILES / WITH NEW HEADERS \

of

Test-Data

EDIT REPORT FILES USED. NOT USED. ETC.

Transmission

1

REFERENCE AND GROUP DATA FILES

I

RITPRG STATISTICAL ANALYSIS

RESULTS TO / BE FORMATTED! L FOR OUTPUT \

DIURPT REPORT GENERATOR

1

£

EXPERIMENTERS PERMANT RECORD

RECORDS FOR ABCD II

RESEARCH INFO PERMANENT RECORD

ABCD PROGRAMS

Figure 6.

Flow chart for diuretic data system

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978. Data and control file formats before and after processing by PICK

00024 5 . 7 , 1 5 9 , 9 9 , 1 1 8 , 3 5 . 5 00025 7 , 1 9 4 , 8 0 , 1 4 8 , 3 8 . 8 00026 8 . 2 , 1 8 1 , 4 1 , 1 4 8 , 3 1 . 7 00027 END

00024 5 . 7 , 1 5 9 , 9 9 , 1 1 8 , 3 5 . 5 00025 7 , 1 9 4 , 8 0 , 1 4 8 , 3 8 . 8 00026 8 . 2 , 1 8 1 , 4 1 , 148,31.7 00027 END

Figure 7.

00001 00000 A 00000 770303 0 1 2 00002 8 00003 2 . 2 , 1 2 9 , 1 8 8 , 1 7 4 , 1 9 . 9 00004 2 , 1 1 1 , 6 4 , 1 1 3 , 1 0 . 3 00005 2 . 5 , 1 0 6 , 7 2 , 1 4 1 , 1 2 . 9

00001 "CONTROL SALINE LOAD 5% M NTR 3-3-77" 00002 8 00003 2 . 2 , 1 2 9 , 1 8 8 , 1 7 4 , 1 9 . 9 00004 2 , 1 1 1 , 6 4 , 1 1 3 , 1 0 . 3 00005 2 . 5 , 1 0 6 , 7 2 , 1 4 1 , 1 2 . 9

00001 19349 A 00100 770303 1 1 2 00002 8 00003 1 1 . 5 , 1 1 4 , 4 2 , 1 4 2 , 2 . 6 00004 6 . 8 , 1 7 4 , 7 2 , 2 1 7 , 5 . 1 00005 9 . 6 , 1 4 2 , 5 7 , 1 6 2 , 3 . 9

00024 9 . 8 , 1 1 4 , 8 0 , 1 0 7 , 2 3 . 7 00025 8 . 6 , 1 2 2 , 7 3 , 1 2 0 17.9 00026 6 . 9 , 1 2 4 , 1 2 4 , 7 9 , 3 0 . 3 00027 END

3-3-77"

00024 9 . 8 , 1 1 4 , 8 0 , 1 0 7 , 2 3 . 7 00025 8 . 6 , 1 2 2 , 7 3 , 1 2 0 , 1 7 . 9 00026 6 . 9 , 1 2 4 , 1 2 4 , 7 9 , 3 0 . 3 00027 END

00001 "A-19349 100 MG/KG PO SALINE LOAD 5% M 00002 8 00003 1 1 . 5 , 1 1 4 , 4 2 , 1 4 2 , 2 . 6 00004 6 . 8 , 1 7 4 , 7 2 , 2 1 7 , 5 . 1 00005 9 . 6 , 1 4 2 , 5 7 , 1 6 2 , 3 . 9

0 8 3 6 000000000

0 8 3 6 000000000

2

ο

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g η

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3.

GINSBERG E T A L .

Automation

of Test-Data

Transmission

35

number i n a group. The numerical p o r t i o n o f a data f i l e ' s name and i t s corresponding weight f i l e are i d e n t i c a l . The header l i n e s o f a data f i l e and weight f i l e s e t a l s o are identical. A batch of t e s t f i l e s can be a s s o c i a t e d w i t h a particular control f i l e by comparing a p p r o p r i a t e parameters contained i n the header l i n e s o f these f i l e s . A f t e r some i n i t i a l m a n i p u l a t i n g t o determine which f i l e s are a v a i l a b l e f o r a p a r t i c u l a r p r o c e s s i n g run, the names o f these f i l e s are given t o the' f i r s t mainline program, DURTIC. Taking each f i l e i n t u r n , DURTIC uses the f i l e ' s name and c r e a t i o n date t o determine i f i t was p r e v i o u s l y processed, i . e . , d u r i n g the l a s t processing r u n . T h i s i s accomplished by comparing the f i l e name and c r e a t i o n date f o r each new f i l e a g a i n s t the name and date f o r p r e v i o u s l y used f i l e s . Since t h e same f i l e name could conceivably be used many times, i t i s important t o i n c l u d e t e s t . I f the f i l e wa i n d i c a t o r f o r t h a t f i l e and ignores i t f o r the remainder of the run. I f the f i l e had not been used p r e v i o u s l y , subroutine PICK i s c a l l e d t o decipher the contents o f the header l i n e . The s t r a t e g y employed i n PICK c o n s i s t s of l o o k i n g f o r keywords, phrases, or patterns o f characters i n the alphanumeric s t r i n g t o determine the value of necessary parameters. The one assumption made was that each v a r i a b l e i n the l i n e must be entered i n a c o n s i s t e n t manner; f o r example, the compound number must be given as A - 1 9 3 4 9 not A 1 9 3 * * 9 o r 1 9 3 ^ 9 - A , e t c . A l l r e q u i r e d c h a r a c t e r s t r i n g s are s p e c i f i e d i n t h e program. However, depending on t h e nature of the f i l e , whether i t c o n t a i n s c o n t r o l data or data on a t e s t compound, some s t r i n g s will not be searched f o r . I f a header l i n e does not meet a l l the s p e c i f i e d c r i t e r i a , an e r r o r f l a g i s s e t and t h e f i l e i s ignored d u r i n g the remainder of the p r o c e s s i n g run. Numerous e r r o r checks were b u i l t i n t o the programs. Only i f the data s e t s passed every t e s t would the experimental r e s u l t s be p r i n t e d f o r review and entry i n t o t h e corporate data base. These checks i n c l u d e : 1. the

Exact matching o f s i x parameters i n the header l i n e s o f data and weight f i l e s f o r each experiment,

2. Exact matching o f a p p l i c a b l e parameters i n the headers for drug and c o n t r o l f i l e s f o r any day's experiments, 3. Matching, w i t h i n l i m i t s , the f i l e ' s c r e a t i o n a l l data s e t s i n a group, 4. Matching numbers o f animals vs. o b s e r v a t i o n s , and 5.

date f o r

the number o f recorded

Matching numbers of o b s e r v a t i o n s f o r c o n t r o l

and drug

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

36

RETRIEVAL

data s e t s f o r each s t a t i s t i c a l

OF

MEDICINAL

CHEMICAL

INFORMATION

analysis set.

Output from DURTIC c o n s i s t s of an e d i t report of f i l e s used, not used, e t c . , a f i l e f o r i n p u t t o t h e next run c o n t a i n i n g the names and c r e a t i o n dates of a l l f i l e s processed t h i s run and not t o be reused, and a f i l e c o n t a i n i n g the names of the f i l e s ready t o be acted upon i n module 2, s o r t e d i n t o a p p r o p r i a t e groups. During the course o f the d i u r e t i c s c r e e n i n g p r o j e c t , s e v e r a l BASIC programs had been used by the i n v e s t i g a t o r s t o analyze data f o r t h e v a r i o u s time periods at which samples were collected. A t d i f f e r e n t times d u r i n g t h e s c r e e n i n g program the number o f chemical assays performed on each sample a l s o v a r i e d (e.g. u r i c a c i d l e v e l s may or may not have been determined). The h i s t o r i c a l data f i l e s do not c o n t a i n n o t a t i o n s as t o which time periods or assays but these can be a s c e r t a i n e observations t h a t were recorded and t h e date of the experiment. T h i s i s part of the grouping process accomplished i n DURTIC. Following s t a t i s t i c a l a n a l y s i s of the data by the a p p r o p r i a t e program, the f i n a l s t e p i n t h i s process (DIURPT) prepares paper r e p o r t s as w e l l as d i s k f i l e s of the analyzed data formatted f o r entry i n t o t h e master data base. Two p r i n t e d r e p o r t s and one i n t e r m e d i a t e data f i l e c o n t a i n i n g t h e data formatted f o r e n t r y to ABCD are generated by DIURPT. One s e t of r e p o r t s , c o n t a i n i n g t h e d e t a i l e d statistical r e s u l t s i n t a b u l a r form, i s used i n r e p o r t i n g back t o t h e r e s p o n s i b l e i n v e s t i g a t o r (Figure 8). The second r e p o r t i s a l i s t i n g o f t h e data i n t h e format acceptable t o ABCD. During the p r e p a r a t i o n of these r e p o r t s each experiment i s assigned a s e q u e n t i a l experiment number by the computer program DIURPT. The l a s t page of each report contains a t w o - l i n e statement which must be signed and dated by the person who has reviewed the output. T h i s r e l e a s e s the experiments f o r which r e s u l t s have been p r i n t e d i n t h e computer output. This same sequence number i s i n c o r p o r a t e d i n t o t h e data records reformatted f o r t h e corporate computer f i l e s . Both s e t s of r e p o r t s are sent t o t h e pharmacology group f o r review and s i g n a t u r e . Only the copy w i t h the reformatted records i s returned t o t h e Research Information group; the r e s p o n s i b l e i n v e s t i g a t o r keeps the other r e p o r t on file. Upon r e c e i p t of t h i s signed r e c o r d , the data w i l l be r e l e a s e d from the i n t e r m e d i a t e f i l e t o t h e f i l e being b u i l t f o r the next update of the corporate master data base. At t h i s time more than 85% o f the a r c h i v a l t e s t data processed have been acted upon by the programs without manual i n t e r v e n t i o n . The e r r o r checks b u i l t i n t o t h e programs a l s o identify input e r r o r s f o r current experiments. Specific experiments r e j e c t e d by any of the programs are reviewed by the a p p r o p r i a t e i n d i v i d u a l , c o r r e c t i o n s made as r e q u i r e d , and t h e data f l a g g e d f o r r e p r o c e s s i n g .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

3.

GINSBERG E T A L .

Automation

of

Test-Data

37

Transmission

SCREEN 0007t Τ · Τ Ε 3 Τ RESULTS PROM RAT PIURETIC SCREENING DATA OFF OF F A I L S A F E FOR MONTH OF à P * - 7 7 RUN ON 14-FEB-78 VOLUME (ML/KG)

SOOIUM (HEO/KG)

POTASSIUM (HEQ/KG)

CHLORIDE (HEQ/KGJ

Α·19349 1 0 0 . 0 0 MG/KG PO SALINE LÛAO 5X Ν NTR 0 3 - 0 3 - 7 7 0*2 HOURS CONTROL 10,9682 ORUG 29.0217 DELTA 18.0535 2.3*64 6,2710 6.4980 6,5621 T-CALC PROS 0,0000 0.0317 0.0000 0.0000 o-e> HOURS 25,3184 β,7457 5.3350 11.2079 CONTROL 59,3786 21.7706 7.2409 25.0231 ORUG 1.9059 13.8152 13,0249 DELTA 34,0602 10.0319 2.9156 10,0495 11,6807 T»CALC PROB 0,0000 0,0000 0.0000 0,0106 0*24 HOURS 10.2726 20,2672 49,1386 19,7823 CONTROL 62.1130 29,8380 12.3537 31.9110 DRUG DELTA 32,9744 10,0557 11,6438 2.0*11 9.7624 8,1002 2,337? 6.1872 T-CALC 0.034* 0,0000 PROB 0,0000 0,0000 2·6 HOURS 2,7625 6.5274 5.1353 CONTROL 14,3502 13.0482 30,3568 11,7863 3,5197 ORUG 0.7*74 6,5208 6.6510 DELTA 16.0066 9.4229 2.7*17 7.7320 9.5962 T»CALC PROB 0,0000 0,0000 0.0144 0,0000 §•24 HOURS CONTROL DRUG DELTA T-CALC MOB

23,8203 22,7345 •1,0858 •0,3532 0,7292

11.0365 β,0674 -2,9691 •2,2714 0,0394

4.9376 5.Π2Λ 0.1752 0,2Λ2« 0.7BH

9.0592 6,8879 -2.1713 •1,9738 0.0685

PAGE

NA/K RATIO

EXPT

URIC AC 10 (MG/KG)

#00378

6,2469 0.0000

-1.3190 0.2083

1.6776 3.0149 1.3373 9.5873 0,0000

7.0379 5.9875 •1.0504 •3.4965 0,0036

2,0004 2,4113 0,4109 2.4598 0,0275

26.1265 21.0431 •5.0834 -3.5757 0.0030

1,8887 3.3591 1.4705 10.5562 0.0000

4.1634 3.4475 -0.7159 •2.2744 0.0392

2.3939 1.5658 -0.8281 -2,4906 0.0259

19.0886 15.0556 •4.0330 •2.8200 0,0136

KITH THE EXCEPTIONS, \f ANY, NOTED BELOW FXPERIHENTS §00368 · #00381 ARE OK FOR ENTRY INTO ABCO I I

Figure 8.

, -, 8I6NE0

9

— — DATE

Sample statistical report

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

38

Summary The two approaches described in this paper for automation of test data transmission from the source to a computer master file have decreased the cost of data entry and increased the accuracy of data recording. With a totally computerized operation, changes in experimental parameters and/or statistical calculations on raw data can be accomodated by modification of the programs. This allows the scientist flexibility in recording results of revised experimental procedures. Abstract In order to eliminate, wherever possible, keypunching of large volumes of data per experiment or transcription of results obtained from computer statistical calculations, the experimenters enter origina computer terminal. A l controlled by computer programs; humans intervene only when required for visual evaluation of the information or approval of outputted results. This approach is cost effective and ensures producer responsibility for recorded information. Two methods are discussed: 1. Direct recording of observations (e.g. plant growth) on a portable battery powered recording device, followed by data transmission to and further processing on the R&D computer; and 2. CRT entry of observed values for test and control animals for specific tests, followed by appropriate statistical calculations with report generation and simultaneous reformatting of summary information for the corporate master data base (ABCD). Only after verification of the accuracy of the data by the producers of the information are the results entered into the master data base. Acknowledgements The authors wish to thank the following for their assistance and cooperation in these projects: Dr. Amrit L a l l , Patricia Morse, Karen Oheim, Douglas Reno, and Donald Weber. Literature Cited 1. J.

Morphis, Β. B , Torbet, Ν . , Hunter, W. W., and Broome, F . K., Chem. Doc. (1966) 6, 77-81.

2. Ginsberg, H. F., G r e t h , P . Α . , and Morphis, B . B.,"ABCD II A User C o n t r o l l e d Biological - Chemical Data System," Presented before the Division of Chemical Literature, ACS, New York, N.Y., August 28, 1972. 3.

Federal R e g i s t e r , November 19, 1976, 41 (225), 51206-51229.

4. MSI Data C o r p o r a t i o n , 340 F i s c h e r 92627

Avenue,

Costa

Mesa, CA

RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

4

C l u s t e r i n g in F r e e - T e x t D a t a Bases

RUDOLPH J. MARCUS, EDWIN T. FLORANCE, and EUGENE E. GLOYE Office of Naval Research, 1030 East Green Street, Pasadena,CA91106

In previous paper th author hav demonstrated th utility of t e x t h a n d l i n g method structural i n f o r m a t i o n . Although the methods developed have general applicability, the particular data base used was one composed of medical and chemical information and led to heuristic structure-activity correlations. Specifically, the data base c o n s i s t s of all of the e n t r i e s from the eighth e d i t i o n of the Merck Index which list a medical use. There are 3,433 such compounds. For each of them we have listed all of the medical uses as well as all of the synonyms by which these compounds are known. In a d d i t i o n t o trade names, these synonyms c o n t a i n one or more Geneva system names. These Geneva system names c o n t a i n the "structural" i n f o r m a t i o n . (The Geneva system of nomenclature has been u n i v e r s a l l y used by chemists s i n c e 1864 and is kept up-to-date as new nomenclatural exigencies arise. In the Geneva system, each syllable u n i q u e l y defines a structural module of a m o l e c u l e , and the position of the syllable in the name tells how the modules fit together i n the m o l e c u l e . ) I t i s the m a n i p u l a t i o n of v a r i o u s Geneva system names as t e x t which c o n s t i t u t e s part of the n o v e l t y of our work. M a t e r i a l q u a l i f y i n g the medical use terms such as a former use or an experimental use has been coded i n t o the data base. Intere s t i n g c o n c l u s i o n s from the d i s t r i b u t i o n of such use q u a l i f i e r s w i l l be l i s t e d below. I t i s seen, then, that our data base i s a c l o s e d , s e l f - c o n s i s t e n t u n i v e r s e which i s not updated. Simple r e t r i e v a l i s p o s s i b l e by searching e i t h e r by s t r u c t u r a l module or by medical u s e . Exhaustive study of the medical use part of the data base began w i t h the counting of uses and the concurrent c o m p i l a t i o n of an i n v e r t e d Merck Index which could be entered by medical use r a t h e r than by chemical compound. In that manner a " s o c i o l o g y " of medical use language was derived (1). Because both medical use and chemical s t r u c t u r e are assoc i a t e d i n the same computer f i l e , they form a hyperspace. The nonparametric nature of t h i s hyperspace was discussed i n a This chapter not subject to U.S. copyright. Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

40

O F MEDICINAL

CHEMICAL

INFORMATION

previous paper (2) and a r i s e s from the n a t u r a l language t e x t , r a t h e r than n u m e r i c a l , nature (alphanumeric r a t h e r than numeric) of the data base. C l u s t e r s i n such t e x t systems were defined i n that paper as a c o l l e c t i o n of v e c t o r s whose column elements are s i m i l a r . Mutual e x c l u s i v i t y , where the column elements of the v e c t o r s are d i s s i m i l a r , was a l s o found to be an e f f e c t i v e b a s i s of i d e n t i f y i n g c l u s t e r s . While the d e f i n i t i o n and i d e n t i f i c a t i o n of c l u s t e r s i n a t e x t data base was s a t i s f y i n g , no q u a n t i t a t i v e i n f o r m a t i o n about the closeness of elements w i t h i n the c l u s t e r or about the goodness of f i t could be obtained w i t h those d e f i n i t i o n s . The present paper, t h e r e f o r e , addresses these questions. D i s t r i b u t i o n of Uses The medical use data f i l e which i s being analyzed has been e x t r a c t e d from the mai Merck Index s i s t s of l i n e r e c o r d s f i r s t f i e l d i s a f o u r - d i g i t code number r e p r e s e n t i n g a unique chemical compound. The second f i e l d i s a l e t t e r c h a r a c t e r symb o l i z i n g a s p e c i f i c q u a l i f i e r a p p l i e d to the g i v e n medical use. Table I gives the 10 q u a l i f i e r s coded i n t h i s f a s h i o n . Note that the l e t t e r X denotes the set of uses without any q u a l i f i c a t i o n . The t h i r d f i e l d i s the name of the medical use expressed as an alphanumeric s t r i n g of c h a r a c t e r s . In f u r t h e r m a n i p u l a t i o n of the use data f i l e , the counting procedures and concepts of numerical l i n g u i s t i c s w i l l be used e x t e n s i v e l y . Although t h i s a p p l i c a t i o n of l i n g u i s t i c s to a data base not c o n t a i n i n g the u s u a l n a t u r a l language t e x t may seem odd, there are s e v e r a l advantages i n doing so. F i r s t , the methods already developed i n other contexts may be a p p l i e d without subs t a n t i a l reprogramming. Second, when the data base i s viewed l i n g u i s t i c a l l y , i t s s i m i l a r i t i e s or d i f f e r e n c e s w i t h other l i n g u i s t i c data can lead to hypotheses about how the data were generated. In other words, the r u l e s f o r naming medical uses w i l l be compared w i t h the naming r u l e s used i n o r d i n a r y language. T h i r d , there i s some i n d i c a t i o n that the problems of indexing and r e t r i e v i n g can be b e t t e r understood i n t h i s context i f the data base i s t r e a t e d as i f i t were normal t e x t used f o r b i b l i o graphic purposes; t h a t i s , e i t h e r as key words o r as a b s t r a c t s . To i n t r o d u c e important concepts, then, i t i s f i r s t necessary to d i s t i n g u i s h between a s p e c i f i c use name found i n the data base and a l l occurrences o f t h a t s p e c i f i c name. The s p e c i f i c name i t s e l f w i l l be c a l l e d a use type> w h i l e any s i n g l e occurrence of t h a t name w i l l be c a l l e d a use token. Thus, i f the use narcotic occurs 48 times i n the data base, then t h a t set could be d e s c r i b e d as 48 use tokens; o r , on the other hand, i t could be d e s c r i b e d as the use type narcotic having a frequency of 48 i n the data base. This usage i s very convenient f o r counting purposes. The data base contains 3433 chemical compounds. There are

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

4.

MARCUS E T AL.

Free-Text

Data

Bases

TABLE I

SPECIFIC QUALIFIERS GIVEN TO MEDICAL USES IN THE MERCK INDEX

X

N u l l Character

Ζ

A d d i t i o n a l Information

Η

Has been used

F

Formerly

A

A c t i v i t y , Properties

Ε

Experimental

I

Has been i n v e s t i g a t e d , has been s t u d i e d , i n v e s t i g a t i v e , has been t r i e d as

Ρ

Proposed as

R

Reportedly causes

S

O c c a s i o n a l l y a s , sometimes as

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

41

42

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

949 d i s t i n c t medical uses, or use types, mentioned i n the use f i l e . But s i n c e each compound may have more than one d i f f e r e n t use, the t o t a l number of use tokens i s expected t o be l a r g e r than the t o t a l number of compounds. In f a c t , there are 4848 use tokens i n the f i l e , which represents about 1.4 uses on the average f o r a t y p i c a l compound. Hence, each use type occurs on the average of about 5.1 times; that i s , there are over 5 use tokens for each t y p i c a l use type. S t a t i s t i c s l i k e those j u s t c i t e d — a v e r a g e number of uses per compound or average use tokens per t y p e — a p p l y t o the e n t i r e data base and g i v e some n o t i o n of gross p r o p e r t i e s . But more d e t a i l e d s t r u c t u r e s can be measured and w i l l g i v e a b e t t e r p i c ture of the naming r u l e s which l e d t o assignment of use names. In f a c t , more can be learned by p a r t i t i o n i n g the data s e t i n t o s m a l l e r subsets and c a l c u l a t i n g the p r o p e r t i e s of these d i v i s i o n s . To the extent t h a t thes whole f i l e , i t i s p o s s i b l a s i g n i f i c a n t a n a l y t i c a l o p e r a t i o n on the data. Use Combinations. Each compound i n the data base has one or more d i s t i n c t use names a s s o c i a t e d w i t h i t . For some compounds, the s e t of names may c o n t a i n two that are the same but whose ( l e t t e r ) q u a l i f i e r s are d i f f e r e n t . These d i f f e r e n t l y q u a l i f i e d use names w i l l be considered as d i f f e r e n t use names f o r the purpose of t h i s i n v e s t i g a t i o n . Thus, each compound can be assigned an i n t e g e r which denotes how many d i s t i n c t use tokens are a s s o c i a t e d w i t h i t . This i n t e g e r , which measures uses per compound, can a l s o be assigned t o each use token a s s o c i a t e d w i t h the given compound. In the data base, the number of uses per compound v a r i e s g e n e r a l l y up t o 6, but there are a s p e c i a l s e t of compounds which have 9 a s s o c i a t e d uses each. The f i r s t r e s t r u c t u r i n g of the data f i l e c o n s i s t e d , then, i n a s s i g n i n g a uses-per-compound i n t e g e r t o a l l use tokens and an assignment of a code number t o each use type. This l a t t e r assignment was made by l e t t i n g the most frequent use type have the lowest code number. The data f i l e was f u r t h e r reorganized by combining a l l use tokens (now represented by code numbers) for a given compound on the same l i n e i n ascending numerical order. Thus, the 4848-line f i l e was reduced t o a 3433-line f i l e . Only the use q u a l i f i e r data was removed. The r e s u l t i n g f i l e was then s o r t e d by uses per compound and s e c o n d a r i l y by the p a r t i c u l a r combination of uses. F i n a l l y , a counting program was used to e l i m i n a t e compound numbers and group together a l l s i m i l a r use combinations. This p a r t i t i o n i n g of the main f i l e i n t o subsets w i t h d i f f e r ent values of uses per compound (that i s , s i z e of the use combinat i o n s e t ) provided some s t a t i s t i c s on how m u l t i p l e uses are d i s t r i b u t e d . Table I I presents the summary data. I t shows how the number of compounds and use tokens are d i s t r i b u t e d over the uses/compound parameter. The column l a b e l e d "use types"

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

4.

MARCUS E T A L .

Free-Text

Data

43

Bases

TABLE I I

MULTIPLE USE TABLE SUMMARY DATA D i s t r i b u t i o n of Number of Compounds and Their Occurrence Over the Uses/Compound Parameter

Uses/ Compound

Number Of Compounds

Use Tokens (Occurrences)

Use Types (Descriptors)

D i s t i n c t Use Combinations

1

2447

2447

570

570

2

717

1434

414

391

3

187

561

231

133

4

60

240

140

46

5

5

25

21

5

6

4

24

20

4

9

13

117

10

2

3433

4848

TOTALS

1151

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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gives the number of use types which appear i n each subset. Since the p a r t i t i o n i n g i s o v e r l a p p i n g i n use types, the numbers i n that column cannot be added t o give a t o t a l . The l a s t column i n d i cates how many d i s t i n c t l y d i f f e r e n t use combinations there are w i t h a given combination s i z e . For example, each compound w i t h 5 or 6 uses has a d i s t i n c t s e t of a s s o c i a t e d uses, w h i l e 9-use compounds have only 2 d i s t i n c t s e t s . Since use combinations are p a r t i t i o n e d i n a non-overlapping f a s h i o n , a sum of the column e n t r i e s gives 1151 as the t o t a l d i s t i n g u i s h a b l e number of use combinations. Thus, on the average, each use combination i s a s s o c i a t e d w i t h about 3 d i f f e r e n t compounds. In one v e r s i o n of the f i l e s o r t e d on use combination, a l l use s e t s beginning w i t h the same use are grouped together, r e g a r d l e s s of the s i z e of d i f f e r e n t combinations. This format permits comparison of use combinations c o n t a i n i n g the same p a i r s of uses. An e y e b a l l search, w i t t a b u l a t e the most frequen Table I I I i n c l u d e s a l l use p a i r s w i t h a frequency of occurrence g r e a t e r than 5. The p a i r names and frequency of occurrence are presented i n the t a b l e , as w e l l as the d i s t r i b u t i o n of these p a i r s over d i f f e r e n t s i z e combinations. For example, the use p a i r analgesia-sedative occurs three times as a p a i r but a l s o i n three t r i p l e combinations w i t h other uses: h y p n o t i c , n a r c o t i c , and s k e l e t a l muscle r e l a x a n t . The e n t r i e s i n Table I I I have been grouped by closeness o f r e l a t i o n . I n a taxonomic sense, the grouped p a r t s c o n s t i t u t e a c l u s t e r . The f i r s t e i g h t e n t r i e s represent an a n a l g e s i c - s e d a t i v e c l u s t e r , which i n c l u d e s the use names analgésie or sedative. The next four t a b l e e n t r i e s represent an a n t i s e p t i c - a s t r i n g e n t c l u s t e r . The cardiotonic-cardiac rate decrease p a i r i s i s o l a t e d and seems t o suggest synonymity. The next f i v e e n t r i e s are a c l u s t e r centered on the diuretic'-antihypertensive pair. Proceeding f u r t h e r down the t a b l e , one encounters a c l u s t e r based on a t r i p l e of uses: a d r e n o c o r t i c a l s t e r o i d , g l u c o c o r t i c o i d , a n t i - i n f l a m m a t o r y . The parasympathomimetic-miotic c l u s t e r occurs alone, f o l l o w e d by a c l u s t e r centered on sympathomimetic. Use-Oriented Data. To i n v e s t i g a t e r e l a t e d uses, the data base was r e s t r u c t u r e d t o p l a c e a l l uses a s s o c i a t e d w i t h a given compound together i n the same record (or e q u i v a l e n t l y on the same t e x t l i n e ) . But other i n f o r m a t i o n may be obtained by grouping together a l l tokens o f the same use type. I n a f i l e whose records c o n s i s t o f the compound code, the uses-per-compound parameter, the q u a l i f i e r code, and the use name, a simple alphanumeric s o r t on use name b r i n g s together a l l use tokens of the same type. The r e s u l t i n g f i l e can then be f u r t h e r s o r t e d on e i t h e r uses per compound or q u a l i f i e r code. From these sorted f i l e s , which s t i l l c o n t a i n compound codes, a summary t a b l e can be prepared by removing compound r e f e r e n c e s . I n such a t a b l e , each r e c o r d or t a b l e l i n e contains a count of a l l use tokens

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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TABLE I I I

DOMINANT USE PAIRS

Uses/Compound

29 27 3 4 6 3 54 4 14 12 4 6

_3

4_

>5

12 5

1 1

14

5 4 1 3 3 7

10 1

P a i r Names

56 33 10 9

analgesic, a n t i p y r e t i c analgesic, narcotic analgesic, anesthetic a n a l g e s i c , antirheumatic

6 58 11

analgesic, sedative s e d a t i v e , hypnotic sedative, t r a n q u i l i z e r

26 13 6 8

antiseptic, antiseptic, antiseptic, astringent,

22

cardiotonic, cardiac rate decrease d i u r e t i c , smooth muscle relaxant d i u r e t i c , myocardial stimulant d i u r e t i c , antihypertensive diuretic, vasodilator a n t i h y p e r t e n s i v e , ganglion b l o c k i n g agent

1

1

12 1 1 2

1

22

15

7

22

14

7

21

7

14 7 12

14 10

Freq.

2

8

6

1

15

4

6

1

11

5

2

1

4 5 4

2 1 2

astringent disinfectant expectorant styptic

adrenocortical steroid, glucocorticoid adrenocortical steroid, anti-inflammatory

8

parasympathomimetic, miotic

6 6 6

sympathomimetic, v a s o c o n s t r i c t o r sympathomimetic, CNS stimulant sympathomimetic, decongestant

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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(occurrences) of a given type (the frequency of t h a t type) together w i t h the use name. Separate columns then present counts of the numbers of use tokens appropriate t o each value of the secondary s o r t parameter. Table IV presents a sample of such a t a b u l a r p r e s e n t a t i o n f o r uses per compound. Note that the t a b l e has been sorted so that the most frequent uses occur f i r s t i n the t a b l e . The type of data f i l e d i s p l a y e d i n Table IV resembles a concordance i n the sense that i t shows occurrences of d i f f e r e n t words i n d i f f e r e n t subclasses or t e x t s . In most l i n g u i s t i c s t u d i e s , the columns represent d i f f e r e n t t e x t s , and the t a b l e e n t r i e s denote counts of word tokens i n those t e x t s . We w i l l use the d e s c r i p t i o n " t e x t " here to denote one of these columns even though no t e x t has been d e f i n e d ; r a t h e r , " t e x t " means a p a r t i t i o n i n g of the data. The e n t i r e t a b l e w i l l be c a l l e d a word d i s t r i b u t i o n t a b l e r i n g t o these p a r t i c u l a An i n s p e c t i o n of Table IV r e v e a l s that there appear t o be two d i s t i n c t i v e l y d i f f e r e n t c l a s s e s of use types as revealed by the d i s t r i b u t i o n of tokens w i t h the parameter uses/compound. A comparison of antimicrobial w i t h analgesic i s i n s t r u c t i v e . Antimicrobial has the l a r g e s t number of s i n g l e uses (201) i n the f i l e and has only 25 m u l t i p l e uses. I t a l s o describes no compounds w i t h more than three uses. This suggests e i t h e r t h a t compounds w i t h a n t i m i c r o b i a l p r o p e r t i e s are h i g h l y s p e c i f i c o r that the name i s a p p l i e d very s p e c i f i c a l l y . In c o n t r a s t , analgesic has only 55 s i n g l e uses, but 119 m u l t i p l e uses. I n f a c t , one compound w i t h a n a l g e s i c p r o p e r t i e s has s i x uses. T h i s suggests e i t h e r that compounds w i t h a n a l g e s i c p r o p e r t i e s a r e r a t h e r nons p e c i f i c and g e n e r a l i z e d i n t h e i r a c t i o n or t h a t the name analgesic r e f e r s t o a r a t h e r wide range of e f f e c t s . These examples appear t o suggest t h a t , by examining the d i s t r i b u t i o n of tokens w i t h the uses-per-compound parameter, the uses can be e i t h e r p a r t i t i o n e d i n t o s p e c i f i c and n o n s p e c i f i c c l a s s e s or described by a s p e c i f i c i t y parameter. Frequency D i s t r i b u t i o n . The word d i s t r i b u t i o n t a b l e prov i d e s not only the d i s t r i b u t i o n of word tokens among the v a r i o u s t e x t s but a l s o the t o t a l frequency of each word type. The t o t a l number of types or tokens having a given frequency can be d e t e r mined by simply counting types i n the d i s t r i b u t i o n t a b l e or summing the t o t a l number of tokens w i t h that frequency. The f u n c t i o n s which present the number of types or tokens of a given frequency are c a l l e d , r e s p e c t i v e l y , the type and token distribution functions. In general word s t a t i s t i c s , the type frequency d i s t r i b u t i o n i s a s t e e p l y decreasing f u n c t i o n of frequency; the s i n g l y o c c u r r i n g words c o n s t i t u t e between 25% and 40% o f the t o t a l number of types. A t frequencies greater than 30 o r 40 ( f o r a s m a l l corpus), the type d i s t r i b u t i o n f u n c t i o n i s zero a t many

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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TABLE IV USE DISTRIBUTION FILE Frequency Sort f o r Uses Per Compound Uses/Compound 1 201 93 55 30 47 54 22 71 52 46 58 19 5 27 13 14 29 15 12 23 29 35 40 27 23 32 12 16 10 23 12 5 22 14 14 21 20 23 2

2

3

24 55 82 72 36 23 59 10 10 20 10 32 33 32 22 29 16 20 29 8 11 8 1 5 10 1 24 7 13 9 12 3 7 14 7 5 3 1 1

1 24 21 15 22 7 4 1 3 7 2 17 12 3 12 4 5 8 6 1 4 1 4 5 2 1 6 6 2 6 16 1 2 4

4

6

1 2 3 9 2 2

1

1 1

2 1

13

1

2

10

1 1

2

13

6 4

2

3 1 1 1

2

1

13

3 1 3 1 9 2 1 7

2

7

2 1

2

Use Name

9

2

1 14

Freq.

5

226 175 174 120 117

82 79 73 70 69 66 62 56 51 50 48 48 46 45 44 41 39 39 38 38 38 35 35 31 31 30 30 27 26 24 24 24

antimicrobial antiseptic analgesic sedative diuretic

antineoplastic anesthetic tranquilizer antihistaminic astringent antipyretic an t ihyρ ertens i v e expectorant sympathomimetic anthelmintic carminative narcotic antimalarial antitussive antituberculous x-ray c o n t r a s t medium cathartic CNS s t i m u l a n t anesthetic l o c a l cardiotonic vasodilator counterirritant laxative adrenocortical steroid smooth muscle r e l a x a n t amebicide ganglion b l o c k i n g agent parasympathomimet i c v a s o d i l a t o r coronary antifungal estrogenic myocardial s t i m u l a n t

American Chemical Society Library 1155 16th St. N. W. In Retrieval of Medicinal Chemical Washington, D. C. Information; 20096 Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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frequencies and has v a l u e s between 1 and 5. At l a r g e frequencies the f u n c t i o n i s zero except a t a very few f r e q u e n c i e s . The nature of token frequency d i s t r i b u t i o n f u n c t i o n s i s somewhat d i f f e r e n t , even though f o r l a r g e frequencies they are a l s o nonzero a t the same s e l e c t e d f r e q u e n c i e s . For purposes of a n a l y s i s and modeling, i t i s b e t t e r t o work w i t h cumulative d i s t r i b u t i o n s . Cumulative d i s t r i b u t i o n s a r e formed by summing the frequency f u n c t i o n s f o r a l l f r e q u e n c i e s l e s s than a c e r t a i n value and d i v i d i n g by the t o t a l sum. Cumulative d i s t r i b u t i o n s , when p l o t t e d as a f u n c t i o n of frequency, are S-shaped (ogive) curves, ranging from 0 a t zero frequency t o 1 a t l a r g e frequency. Numerical l i n g u i s t s have made many attempts t o d e s c r i b e or model the word frequency d i s t r i b u t i o n . One of the models which has e x t e n s i v e use i s the log-normal d i s t r i b u t i o n . This model can be d e f i n e d i n terms of the cumulative normal p r o b a b i l i t y d i s t r i b u t i o n . The log-norma lative distribution i the r e s u l t i n g curve conforms t o a normal d i s t r i b u t i o n . The l o g normal d i s t r i b u t i o n d e s c r i b e s many l o n g - t a i l e d d i s t r i b u t i o n s i n l i n g u i s t i c s c i e n c e ; i n p a r t i c u l a r , the d i s t r i b u t i o n s of word l e n g t h and sentence l e n g t h ( 3 ) . Log-normal d i s t r i b u t i o n s are a l s o found i n econometrics and other s o c i a l phenomena ( 4 ) . What gives the log-normal d i s t r i b u t i o n p a r t i c u l a r i n t e r e s t i n word frequency analyses i s t h a t i f the type frequency d i s t r i b u t i o n i s log-normal, then the token frequency d i s t r i b u t i o n i s a l s o log-normal. In p r a c t i c a l terms, t h e type and token cumulative frequency d i s t r i b u t i o n s may be t e s t e d f o r l o g - n o r m a l i t y by p l o t t i n g these f u n c t i o n s on normal p r o b a b i l i t y paper w i t h the l o g a r i t h m of f r e quency as the a b s c i s s a . When t h i s t e s t was a p p l i e d t o the medical use type and token frequency d i s t r i b u t i o n s , the log-normal model was found t o d e s c r i b e both d i s t r i b u t i o n s very w e l l over two orders of magnitude. F i g u r e 1 shows t h i s r e l a t i o n s h i p f o r the use type d i s t r i b u t i o n and a l s o f o r the c l u s t e r type d i s t r i b u t i o n . The c l u s t e r types i n v o l v e a d i f f e r e n t counting than use types, so t h a t two c l u s t e r s a r e the same i f a l l t h e i r components are i d e n t i c a l . The t o t a l number of c l u s t e r types i s simply the sum of the l a s t column i n Table I I . P l o t t e d f o r comparison on F i g u r e 1 are two cumulative d i s t r i b u t i o n s i n which the frequency i s d i s t r i b u t e d normally. Note that the normal curves cannot s a t i s f a c t o r i l y f i t the long t a i l s of the log-normal d i s t r i b u t i o n s . While the normal curves have been chosen somewhat a r b i t r a r i l y t o f i t the observed d i s t r i b u t i o n s a t frequencies of 1 and 22, there i s no c o n s i s t e n t way i n which t o f o r c e a l o g a r i t h m i c curve t o f i t a l i n e a r one. P l o t t e d i n F i g u r e 2 a r e the cumulative type frequency d i s t r i b u t i o n s f o r two subsets of the data base. The s i n g l e use curve corresponds t o a l l compounds w i t h a s i n g l e use. The X curve corresponds t o a l l uses w i t h the X ( n u l l ) q u a l i f i e r ; i . e . , a l l uses which are u n q u a l i f i e d . These subsets a r e a l s o seen t o

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Figure 1. Log-normality of type distribution. Points are plotted on a log frequency scale; curves represent a normal, rather than log-nor mal, distribution in frequency. Cluster types, O ; use types, ·. Normal curve vs. frequency fit to data: clusters, ; uses, . 10

Log φ Frequency

Figure 2. Log-normality of data base subsets. Points are plotted on a log frequency scale; curve represents a normal, rather than log-nor mal, distribution in frequency. Single uses, ·; X uses (no qualifier), O . Normal curve vs. fre quency fit to single-use data. l0

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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be log-normally d i s t r i b u t e d . The f a c t that the use frequency d i s t r i b u t i o n conforms so c l o s e l y to the log-normal was unexpected, inasmuch as the s t a t i s t i c a l " r u l e s " which operate i n n a t u r a l language t e x t would not n e c e s s a r i l y be assumed to operate f o r a corpus of terms derived from a h i g h l y t e c h n i c a l area of s p e c i a l t y such as pharmacology. However, the f i n d i n g suggests that the Merck Index medical use data base does not d i f f e r s u b s t a n t i a l l y i n i t s l i n g u i s t i c prope r t i e s from n a t u r a l language data bases. This r e s u l t i s c o n s i s tent w i t h s t u d i e s of d i s e a s e i d e n t i f i c a t i o n , which a l s o i n v o l v e s a p r o f e s s i o n a l code of terms (3). S p e c i f i c i t y . Several attempts were made t o develop a nonparametric s t a t i s t i c a l d e s c r i p t i o n of the s p e c i f i c i t y q u e s t i o n , based on techniques from numerical l i n g u i s t i c s . I t was hoped that s e t s of very s p e c i f i n a t u r a l l y emerge i n th simple parametric s t a t i s t i c d i d f a r b e t t e r than nonparametric ones: the mean uses per compound f o r each use. The mean uses per compound f o r the e n t i r e data base (excluding 13 compounds w i t h 9 uses, which represent a s p e c i a l case) i s c a l c u l a t e d to be 1.739. The d i f f e r e n c e between the p o p u l a t i o n mean and the mean f o r any use can be t e s t e d f o r s i g n i f i c a n c e by comparison to the standard d e v i a t i o n . For a l a r g e use frequency, N, the mean uses per compound, û", i s d i s t r i b u t e d normally w i t h a s t a n dard d e v i a t i o n given by σ = (.899/N)

15

F i g u r e 3 shows the d i s t r i b u t i o n of values of û f o r f r e quencies of 6 or g r e a t e r . The curves r e p r e s e n t i n g ±2o and ±3σ l i m i t s about the p o p u l a t i o n mean are a l s o shown. From t h i s f i g u r e , 25 uses were found f o r which û d i f f e r e d by 3o from the p o p u l a t i o n mean. Eight uses have s i g n i f i c a n t l y low û: seventeen uses have s i g n i f i c a n t l y h i g h û. L i s t s of these uses w i t h values of û and standard d e v i a t i o n s are given i n Table V. The parameter û was a l s o c a l c u l a t e d f o r the set of compounds corresponding to each use q u a l i f i e r . The s e t s described by q u a l i f i e r s X and Ζ both showed û v a l u e s not s i g n i f i c a n t l y d i f f e r e n t from the t o t a l p o p u l a t i o n . The H and F sets both showed higher than average û. Except f o r the R q u a l i f i e r , the remaining sets a l l had û l e s s than average. Table VI shows these r e s u l t s w i t h combined s e t s to increase s i g n i f i c a n c e . S i g n i f i c a n c e i s denoted by c a l c u l a t e d σ d e v i a t i o n s from the p o p u l a t i o n mean. In t h i s t a b l e , X and Ζ are average, Η and F combined have s i g n i f i c a n t l y h i g h e r uses/compound, and the remaining combination has s i g n i f i c a n t l y lower uses/compound. Thus X and Ζ compounds seem t y p i c a l of the average com pound i n the data base, w h i l e a compound w i t h an Η or F q u a l i f i e r has s i g n i f i c a n t l y more uses than average. This r e s u l t suggests

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

Figure 3. Distribution of mean uses per compound. Outliers are identified in Table V. Poputotion mean, ; 2 σ deviation, ; 3 σ deviation, .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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TABLE V

USES HAVING SIGNIFICANT SPECIFICITY PARAMETER

Mean Uses Per Compound

Use Name

D e v i a t i o n From P o p u l a t i o n Mean (In Q ' S )

Low Mean Uses/Compound antimicrobial antineoplastic antihistaminic antituberculous x-ray c o n t r a s t medium anesthetic l o c a l estrogenic anemia i r o n d e f i c i e n c y

1.11 1.14 1.200 1.227 1.024 1.143 1.042 1.000

4.8 3.6 4.8 3.7 3.6 3.1

High Mean Uses/Compound diuretic antipyretic expectorant vasodilator counterirritant smooth muscle r e l a x a n t myocardial s t i m u l a n t antirheumatic glucocorticoid mydriatic CNS depressant decongestant diaphoretic carbonic anhydrase inhibitor dermatides dermatoses sudorific

2.026 2.321 2.375 2.211 2.400 2.806 3.083 2.591 2.500 2.750 2.700 2.700 2.700

3.3 4.5 5.0 3.1 4.1 6.3 6.9 4.2 3.3 3.7 3.2 3.2 3.2

2.778 2.857 3.167 3.167

3.3 3.1 3.7 3.7

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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e i t h e r t h a t compounds w i t h many uses tend t o have more " o l d " uses or t h a t " o l d " use names tended t o be l e s s s p e c i f i c . The remain ing q u a l i f i e r group has s i g n i f i c a n t l y fewer uses than average, which suggests e i t h e r that compounds w i t h "new" medical uses tend to be l a b e l e d w i t h only one use or that "new" d e s c r i p t o r s are more s p e c i f i c . Discussion We have d e s c r i b e d i n the preceeding s e c t i o n four d i f f e r e n t cuts through the hyperspace of medical uses and t h e i r frequency i n the Merck Index data base. By " c u t " we r e f e r by analogy t o a p r o j e c t i o n of the hyperspace onto one or more r e c o g n i z a b l e orthogonal C a r t e s i a n axes. I n t h i s s e c t i o n we w i l l d i s c u s s what we have learned from these four c u t s . We w i l l a l s o approach, but c e r t a i n l y not exhaust e f f e c t space) w i t h th ture of compounds having these uses (the s t r u c t u r e space). Use Frequencies. One cut through the data base i s t o p l o t the frequency d i s t r i b u t i o n of the medical uses and v a r i o u s major subsets t h e r e o f . We show i n F i g u r e s 1 and 2 t h a t the cumulative d i s t r i b u t i o n of both use types ( d e s c r i p t o r s ) and use tokens (occurrances) i s log-normal. Two major subsets of the data base a l s o have a log-normal d i s t r i b u t i o n . This type of d i s t r i b u t i o n shows that the vocabulary of t h i s unique t e x t i s , c o n t r a r y t o what might have been expected, no d i f f e r e n t from any other t e x t which has been considered by numerical l i n g u i s t s . The log-normal d i s t r i b u t i o n found by numerical l i n g u i s t s a p p l i e s not o n l y t o v o c a b u l a r i e s i n v o l v i n g disease i d e n t i f i c a t i o n , but a p p l i e s t o a number of d i f f e r e n t n a t u r a l language data bases. Mean Uses/Compound. Another c u t through the data base has been made i n terms of mean uses per compound. This parameter has been p l o t t e d a g a i n s t frequency i n F i g u r e 3. I t i s t h i s f i g u r e which permits a f i r s t s t a t i s t i c a l e v a l u a t i o n of the s i g n i f i c a n c e of c l u s t e r s o c c u r r i n g i n t e x t data bases. L i n e s corresponding to two and three standard d e v i a t i o n s (σ) from the mean are drawn i n t o F i g u r e 3, and the v a r i o u s o u t l i e r s on e i t h e r s i d e are l i s t e d i n Table V. The reasons why p a r t i c u l a r uses have low or high mean uses/compound are perhaps best l e f t t o pharmacologists. I t i s r e a d i l y apparent, however, even t o nonpharmacologists, that the uses l i s t e d under low mean uses/compound are h i g h l y s p e c i f i c i n a l i n g u i s t i c , as w e l l as s t a t i s t i c a l , sense. Four of them a r e " a n t i - , " and the other stem of these f o u r words i s a h i g h l y spe c i f i c concept: - m i c r o b i a l , - n e o p l a s t i c , - h i s t a m i n i c , and -tuberculous. Another three uses under low mean uses/compound depend on d i s t i n c t l y chemical p r o p e r t i e s ; these are x-ray con t r a s t medium, anemia i r o n d e f i c i e n c y , and e s t r o g e n i c . Uses l i s t e d under h i g h mean uses/compound seem t o be of two k i n d s . One of

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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these i s the k i n d of use such as d i u r e t i c , v a s o d i l a t o r , smooth muscle r e l a x a n t , myocardial s t i m u l a n t , a n t i p y r e t i c , and expec t o r a n t , which are present i n the dominant use p a i r s , o r c l u s t e r s , l i s t e d i n Table I I I and which w i l l be discussed l a t e r on i n t h i s s e c t i o n . O b v i o u s l y , such compounds would, by t h e i r presence i n these c l u s t e r s , be expected to have more uses per compound than the average. Other uses i n t h i s h i g h mean uses/compound r u b r i c are those use d e s i g n a t i o n s which are o l d e r and perhaps somewhat i m p r e c i s e by more modern d e f i n i t i o n s . This p o i n t w i l l become apparent i n the next paragraph when we d i s c u s s q u a l i f i e r s . Q u a l i f i e r s . A t h i r d cut through the hyperspace was taken on the b a s i s of the q u a l i f i e r s which are defined i n Table I . I t was shown i n Figure 2 that a major subset defined by the use q u a l i f i e r X (a n u l l c h a r a c t e r ) e s s e n t i a l l y followed the same l o g normal d i s t r i b u t i o n a Table V I shows that bot s e t s do not have a s t a t i s t i c a l l y s i g n i f i c a n t d e v i a t i o n from the p o p u l a t i o n mean. However, uses having q u a l i f i e r s Η or P, which represent former uses, have h i g h l y s i g n i f i c a n t (5.3 o) greater mean uses/compound, a f a c t which was a l l u d e d t o i n a d i f f e r e n t context i n the previous paragraph. F o r t u n a t e l y f o r t h i s s t a t i s t i c a l view of the Merck Index data base, the use q u a l i f i e r s A, Ρ, T, P_, P, and S, which represent experimental compounds not yet i n g e n e r a l use, together have fewer mean uses/compound w i t h s t a t i s t i c a l l y h i g h s i g n i f i c a n c e (4.5 σ ) . The d i s c u s s i o n i n t h i s s e c t i o n i n d i c a t e s that not a l l subsets of the data base have the same d i s t r i b u t i o n and that use q u a l i f i e r s , such as those l i s t e d i n Table I , which were f r e q u e n t l y used i n the e i g h t h e d i t i o n of the Merck IndeXj can d i s t i n g u i s h between d i f f e r e n t kinds of med i c a l uses i n a s t a t i s t i c a l l y s i g n i f i c a n t manner. Use C o r r e l a t i o n s . A f o u r t h cut through the medical usefrequency hyperspace i s the one which i n v o l v e s the d e r i v a t i o n of dominant use p a i r s . Table I I I l i s t s these use p a i r s as a f u n c t i o n o f uses/compound. Table I I I a l s o l i s t s the frequency of i n d i v i d u a l use p a i r s . I t was noted e a r l i e r that the use p a i r s i n Table I I I have been grouped by closeness of r e l a t i o n and that i n a taxonomic sense, the grouped p a r t s c o n s t i t u t e a c l u s t e r . The seven c l u s t e r s i d e n t i f i e d are shown i n Table I I I as sepa r a t e d groups of use p a i r s . I t i s t h i s p a r t i c u l a r cut through the data base which suggests the p o s s i b i l i t y of e x t r a p o l a t i o n . Many compounds which have one use contained i n a c l u s t e r might w e l l be examined p h a r m a c o l o g i c a l l y or c l i n i c a l l y t o see whether that compound a l s o has one o r more of the other uses i n that cluster. The same reasoning which suggests t h i s p o s s i b i l i t y of e x t r a p o l a t i o n a l s o leads t o the c o n c l u s i o n that i t i s t h i s p a r t i c u l a r cut through the medical use hyperspace which leads i n t o a s s o c i a t i o n s w i t h the chemical s t r u c t u r e hyperspace.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

1106 255

H + F

+ E + I + P + R+

D e f i n i t i o n s i n Table 1. No 9-use compounds i n c l u d e d .

4731

1062

Ζ

T o t a l Uses**

2308

X

S

No. of Uses

Use Q u a l i f i e r *

1.739

1.490

1.881

1.711

1.711

Mean Uses/Compound

QUALIFIER SUBSETS OF USE TOKENS

TABLE VI

4.5

5.3

1.0

1.5

T

(In Q s )

D e v i a t i o n From P o p u l a t i o n Mean

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Ideally, each of the uses i n Table I I I can be associated with a particular chemical structure. In previous work (1) we have shown that such associations can be made not only by pharmacolog i s t s , working from laboratory data and current theories, but also by text manipulation of the kind which we have described here. Thus for example, the effects of compounds i n the sympathomimetic cluster have been ascribed to the presence of the ethylamine grouping, while the effect of compounds i n the parasympathomimetic cluster have been ascribed to compounds containing the ammonium ion structure or its phosphorus analog. The compounds in the adrenocortical steroid cluster have similar chemical structures by d e f i n i t i o n . The cardiotonic cluster contains natural products related to those found i n digitalis and containing similar side chain structures. The antiseptic-astringent cluster contains recognizably caustic compounds. It i s hoped that similar association b mad i th d gesic clusters. The l a t t e r of uses and perhaps those with the greatest variety of d e f i n i tions. It would be interesting to be able to resolve these definitions on the basis of chemical structure as well as numerical l i n g u i s t i c s . Abstract Heuristic clustering methods for text data have been applied to a data base describing chemical compounds with medical uses. Clusters are sets of chemical compounds related by similarity of both chemical structure and a c t i v i t y . Previously discovered clusters in a free-text data base taken from the Merck Index could be described by a 2 x 2 activity-structure matrix. A s t a t i s t i c a l examination of the activity descriptors (medical uses) reveals them to have a log-normal distribution over two frequency decades. Log-normal distributions have been found by workers in other disciplines to be characteristic of random selection from a set of items with fixed limits. An investigation of compounds with more than one medical use revealed that the dominant clusters are labeled with the descriptors analgesic/ sedative, antiseptic/astringent, diuretic/antihypertensive, adrenocortical steroid, parasympathomimetic, and sympathomimetic. Chemical similarities are involved in those clusters based on multiple medical uses as well as in the case of clusters based on the 2 x 2 activity-structure matrix, which involved computer searches on single activity descriptors only. Consideration of multiple medical use clustering assures comprehensiveness and supplements any weakness of purely heuristic searching. The existence of these chemical similarities permits the exploration of new or previously unreported uses of chemical compounds by computer manipulation of text data.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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57

Literature Cited 1. Marcus, R. J. and Gloye, Ε. Ε., "Real-Time I n t e r r o g a tion of Chemical D a t a , " J. Chemical Documentation 11, 163-7 (1971). 2. Marcus, R. J., Gloye, Ε. E., and F l o r a n c e , E . T., "Computer Search of a Free-Text Data Base as a Tool f o r Investi gating S t r u c t u r e - E f f e c t R e l a t i o n s h i p s , " Computers and Chemistry 1, 235-241 (1977). 3. Herdan, G., "The Advanced Theory of Language as Choice and Chance," S p r i n g e r - V e r l a g , New York, N.Y., 1966. 4. M o n t r o l l , E . W. and Badger, L . W . , " I n t r o d u c t i o n to Q u a n t i t a t i v e Aspects of S o c i a l Phenomena," pp. 110-120, Gordon and Breach, New Y o r k , N.Y., 1975. RECEIVED August 29, 1978

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5 CHEMLINE: a Chemical Structure Search Key to Biological Information MELVIN L. SPANN, DONALD J. HUMMEL, ROBERT J. SCHULTHEISZ, SHARON L. VALLEY, and DONALD F. WALKER, JR. Toxicology Information Program, National Library of Medicine, Bethesda, M D 20014 This paper demonstrates the ability of an o n - l i n e chemical d i c t i o n a r y file in a c c e s s i n g computerized files c o n t a i n i n g biological As i n d i c a t e d in Figure 1, CHEMLINE, the N a t i o n a l L i b r a r y o f Medicine's (NLM) interactive, o n - l i n e d i c t i o n a r y file, can be viewed as the focal p o i n t f o r the chemical searching of the Library's on-line literature retrieval s e r v i c e s (1). In a d d i t i o n , CHEMLINE provides a l i n k a g e through a "Locator" d e s i g n a t i o n t o other files c o n t a i n i n g i n f o r m a t i o n r e l e v a n t t o h e a l t h and environmental concerns. An example of the latter is the Environmental P r o t e c t i o n Agency's Toxic Substances C o n t r o l Act (TSCA) Inventory Candidate List. Substances appearing on the Candidate List are referenced w i t h the EPATSCALIST Locator code. This d i s c u s s i o n will be limited t o CHEMLINE's use in connection w i t h the TOXLINE and RTECS files, which are available t o over 800 institutions that subscribe t o NLM's o n - l i n e s e r v i c e s . CHEMLINE CHEMLINE (CHEMical d i c t i o n a r y on-LINE) i s a f i l e of chemical d e s c r i p t o r s created by NLM's Toxicology Information Program i n c o l l a b o r a t i o n w i t h Chemical A b s t r a c t s Service (CAS). This f i l e contains n e a r l y 500,000 chemical substance names r e p r e s e n t i n g over 246,000 unique substances. Because of CHEMLINE's unique f i l e d e s i g n , i t has c a p a b i l i t i e s which support both f u l l s t r u c t u r e and substructure searching. F i g u r e 2 shows a t y p i c a l CHEMLINE u n i t r e c o r d . The f o l l o w i n g s e c t i o n h i g h l i g h t s the c h a r a c t e r i s t i c s of the f i e l d s w i t h i n t h i s r e c o r d , a l l of which are d i r e c t l y searchable (up t o 39 characters) and p r i n t a b l e . RN i s the Chemical A b s t r a c t s Service (CAS) R e g i s t r y Number. This u n i q u e l y assigned number of up t o nine d i g i t s appears i n a hyphenated format without l e a d i n g zeros.

This chapter not subject to U.S. copyright. Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN E T A L .

Figure 1.

RN MF NI NI SY SY SY SY SY SY SY WL NR RS RE CL MH fiH MΚ LO LO LO RC

59

CHEMLINE

NLM's CHEMLINE

file

- 553-24-2 - C15-H16-M.CL-H - C I . BASIC RED 5, MONOHYDROCHLORIDE ( 8 C I ) - 2,8-PHENAZINEDIAMINE, N(8),N(8),3-TRIMETHYL-.M0N0HYnR0CHL0RIDE (9CI) - C I . 50040 - AM I NOD IMETHYLAMI N0T0LUAÎ ι1NOZI NE HYDROCHLORIDE - NEUTRAL RED - TOLUYLENE RED - NEUTRAL RED W - C I . BASIC RED 5 - NUCLEAR FAST RED (BASIC DYE) - Τ C6C6 BN I N J E FZ L N l S l &6H - 3 - 6,6,6 - C4N2-C6-C6 - NC2NC2 - PHENAZINES / ( 6 9 - 7 " ) - DIMETHYLAMIi-iES (73-74) - NEUTRAL RED / (MINOR IM 7 5 ) - TOXLINE - MEDLARS - EPATSCALIST - R089-4926

HCL Figure 2.

CHEMLINE

record

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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MF i s the molecular formula of the compound expressed i n the H i l l convention. T h i s means t h a t , f o r organic compounds, the number of carbon atoms i s c i t e d f i r s t ; t h i s i s f o l l o w e d by the number of hydrogen atoms; and then a l l other elements are c i t e d i n a l p h a b e t i c a l order. For i n o r g a n i c compounds, a l l elements occur i n a l p h a b e t i c a l order. Nl i s the Chemical A b s t r a c t s (CA) p r e f e r r e d index name, i . e . , the s y s t e m a t i c names used i n the Chemical Substance and Formula Indexes of CA. The 8CI and 9CI d e s i g n a t i o n s f o l l o w i n g the two N l names f o r t h i s record i n d i c a t e that the name comes from the E i g h t h C o l l e c t i v e Index P e r i o d (1967-71) and the N i n t h C o l l e c t i v e Index P e r i o d (1972-76) of CA. One can see from t h i s example that the 9CI nomenclature i s c h e m i c a l l y more standardized than the 8CI nomenclature. SY i n d i c a t e s the synonymous names that CAS has on r e c o r d f o r a chemical substance. W i t h i uninverted chemical names mental names, as w e l l as company code numbers f o r chemicals. WL i s the Wiswesser L i n e N o t a t i o n (WLN) f i e l d . The WLN i s a unique and unambiguous r e p r e s e n t a t i o n of a chemical s t r u c t u r e diagram using a l i n e a r arrangement of 36 alphanumeric c h a r a c t e r s , 3 s p e c i a l characters and the blank. There are approximately 10,000 CHEMLINE records that c o n t a i n WLNs. The next s e t of f i e l d s (NR through CL) i n t h i s r e c o r d cont a i n s r i n g i n f o r m a t i o n . Since about 80% of the substances w i t h i n CHEMLINE c o n t a i n r i n g systems, one can see the importance of i n c o r p o r a t i n g t h i s i n f o r m a t i o n i n t o a chemical s t r u c t u r e search system, e s p e c i a l l y f o r substructure searching. NR p r o v i d e s the number of component r i n g s w i t h i n each unique r i n g system i n a chemical substance. As seen i n the diagram, there are 3 r i n g s w i t h i n the phenazine r i n g system. RS g i v e s the s i z e of the component r i n g s w i t h i n each unique r i n g system. For m u l t i p l e r i n g systems, r i n g s i z e s are c i t e d from s m a l l e s t t o l a r g e s t . I n the phenazine r i n g , the r i n g s i z e s are 6,6,6. RE, the Ring Elemental a n a l y s i s f i e l d , contains the molecular formula f o r each component r i n g w i t h i n a unique r i n g system. I n t h i s f i e l d , the element count begins w i t h carbon and a l l other elements (excluding hydrogen) f o l l o w i n a l p h a b e t i c a l order. For a m u l t i p l e - r i n g system, the r i n g elemental a n a l y s i s i s given f i r s t i n order of r i n g s i z e and secondly i n ascending order of the carbon atom count f o r i n d i v i d u a l r i n g s when r i n g s i z e s are equal. Therefore, the RE f i e l d f o r B a s i c Red 5 i s C4N2-C6-C6. Note that t h i s f i e l d i s a l p h a b e t i c a l and does not n e c e s s a r i l y provide the order of occurrence of the component r i n g s w i t h i n a r i n g system.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN

E T AL.

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CHEMLINE

CL i s the Component Line formula f i e l d which provides a t o p o l o g i c a l d e s c r i p t i o n of those r i n g s c o n t a i n i n g between 4 and 8 atoms t h a t a l s o c o n t a i n two or more non-carbon atoms. The r u l e s f o r d e r i v i n g a Component Line formula are as f o l l o w s : 1. 2.

3.

S t a r t a t the e a r l i e s t a l p h a b e t i c non-carbon atom; proceed around the r i n g i n the d i r e c t i o n t h a t provides the s h o r t e s t path t o the next non-carbon atom; and where contiguous atoms r e p e a t , g i v e only the atom and i t s number of occurrences.

Thus, the example shown has the Component Line formula NC2NC2. MH o r the MeSH heading f i e l d contains terms from NLM's M e d i c a l Subject Headings (MeSH) c o n t r o l l e d vocabulary. There are approximately 4,00 LO contains the LOCATO of i n f o r m a t i o n or c i t a t i o n s r e l e v a n t t o the s p e c i f i c chemical substance r e t r i e v e d . CHEMLINE p r e s e n t l y contains l o c a t o r s t o MEDLARS, TOXLINE and EPATSCALIST. A l o c a t o r t o RTECS w i l l soon be added. RC contains the alphanumeric code assigned t o the approx i m a t e l y 33,000 compounds appearing on the EPA TSCA Inventory Candidate L i s t of Chemical Substances. This code should be reported t o EPA, along w i t h the CAS R e g i s t r y Number, t o s a t i s f y TSCA r e p o r t i n g requirements. In a d d i t i o n t o the i n f o r m a t i o n f i e l d s l i s t e d i n F i g u r e 2, there are s e v e r a l searchable but n o n - p r i n t a b l e f i e l d s w i t h i n CHEMLINE records that do not appear i n t h i s f i g u r e . Only two of these f i e l d s which are p a r t i c u l a r l y u s e f u l i n performing sub s t r u c t u r e searches w i l l be d i s c u s s e d . The f i r s t i s the NF or Name Fragment f i e l d . Name fragments are generated by computer programs from the NI (Type 1 name) and SY (Synonym) f i e l d s by breaking a name on hyphens, c o l o n s , enclosures and b l a n k s . Each uniquely o c c u r r i n g character s t r i n g becomes a searchable e n t i t y . Thus, the name fragments f o r the second N l name shown i n Figure 2 are: 2,8 phenazinediamine Ν 8

3 Trimethyl Monohydrochloride

The contents of the second fragment f i e l d , FF, are the molecular formula fragments which are d e r i v e d by breaking the molecular formula on hyphens and p e r i o d s . Excluding hydrogen atoms, each elemental symbol and i t s count are s t o r e d as search able e n t i t i e s . I n a d d i t i o n , the elemental symbol without a count i s saved f o r the heteroatoms ( n i t r o g e n , oxygen, phosphorus and s u l f u r ) and the halogens ( f l u o r i n e , c h l o r i n e , bromine and i o d i n e ) .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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This f e a t u r e permits one to search f o r any ( u n s p e c i f i e d ) number of hetero or halogen atoms i n a chemical compound, or f o r a s p e c i f i c number of these atoms. As an example, searching w i t h the formula fragment S would r e t r i e v e a l l substances having a t l e a s t one s u l f u r atom i n i t s s t r u c t u r e ; whereas formula fragment SI would r e t r i e v e records f o r substances having o n l y one s u l f u r atom. The molecular formula fragments r e t a i n e d f o r B a s i c Red 5 a r e : C15 N4 CLl

Ν CL

TOXLINE TOXLINE (TOXicolog c o l l e c t i o n of computerize t o x i c o l o g y 425,000 r e f e r e n c e s (as of 1978) t o p u b l i s h e d human and animal t o x i c i t y s t u d i e s , e f f e c t s of environmental chemicals and p o l l u t a n t s , and adverse drug r e a c t i o n s . TOXLINE covers the p u b l i s h e d l i t e r a t u r e from 1974 forward. Older i n f o r m a t i o n (380,000 r e f e r ences) can be found i n TOXBACK, which i s searchable i n an o f f l i n e mode. TOXLINE/TOXBACK are made up of component f i l e s that come from the major secondary l i t e r a t u r e sources, as w e l l as s p e c i a l i z e d sources. The c o l l e c t i o n of b i b l i o g r a p h i c c i t a t i o n s a r e obtained e i t h e r through p r o f i l i n g c e r t a i n f i l e s or s e l e c t i n g com p l e t e s p e c i a l t y f i l e s . The sources and extent of coverage of component f i l e s a r e : C h e m i c a l - B i o l o g i c a l A c t i v i t i e s (CBAC) Sections 1-5 from 1965, S e c t i o n s 62-64 from 1975 and Sections 8, 59 and 60 from 1975; T o x i c i t y B i b l i o g r a p h y (TOXBIB) from 1968; A b s t r a c t s on H e a l t h E f f e c t s of Environmental P o l l u t a n t s (HEEP) from 1972; I n t e r n a t i o n a l Pharmaceutical A b s t r a c t s (IPA) from 1970; P e s t i c i d e s A b s t r a c t s (PESTAB, f o r m e r l y HAPAB) from 1966; Environmental Mutagen Information Center (EMIC) f i l e from 1960; Environmental Teratology Information Center (ETIC) from 1950; and the T o x i c M a t e r i a l s Information Center (TMIC) from 1971-1975. In a d d i t i o n , TOXBACK contains a t e r a t o l o g y f i l e (TERA) covering the years 1960-1974 and a s p e c i a l c o l l e c t i o n of l i t e r a t u r e con cerning the h e a l t h e f f e c t s of p e s t i c i d e s , the Hayes F i l e , which covers the p e r i o d from 1940-1966. As i n d i c a t e d i n F i g u r e 3, a l l of these f i l e s are arranged so that they can be searched simultaneously i n response t o a search query; they can a l s o be 'searched independently through use of the f i l e acronym. Each r e c o r d i n TOXLINE contains a f u l l b i b l i o g r a p h i c c i t a t i o n , most have a b s t r a c t s and/or i n d e x i n g terms and CAS R e g i s t r y Numbers. On-line r e t r i e v a l of TOXLINE records i s u s u a l l y accomplished by f r e e - t e x t searching of TEXTWORDS (TW) or

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN E T A L .

63

CHEMLINE

keywords found i n t i t l e s , index f i e l d s or a b s t r a c t s of c i t a t i o n s . Other searchable elements i n c l u d e author name, CAS R e g i s t r y Number, secondary source i d e n t i f i c a t i o n , language, year of p u b l i c a t i o n , and j o u r n a l coden. RTECS While TOXLINE/TOXBACK are b i b l i o g r a p h i c r e t r i e v a l s e r v i c e s , the t h i r d f i l e t o be b r i e f l y d e s c r i b e d i n t h i s paper can be considered an o n - l i n e data r e t r i e v a l f i l e . RTECS ( R e g i s t r y of Toxic E f f e c t s of Chemical Substances) i s a product of the N a t i o n a l I n s t i t u t e f o r Occupational Safety and H e a l t h (NIOSH) and i s a v a i l a b l e as an annual p u b l i c a t i o n (2). NLM o b t a i n s a computer-readable f i l e from NIOSH who maintains r e s p o n s i b i l i t y f o r f i l e contents. The present (1977) v e r s i o n of RTECS contains t o x i c i t y data f o r approximatel provides a d e s c r i p t i o The RTECS f i e l d s i d e n t i f i e d w i t h a search a b b r e v i a t i o n are d i r e c t l y searchable (up t o 36 contiguous c h a r a c t e r s ) . The i n f o r m a t i o n i n the T o x i c i t y Data Index S t r i n g s (IX) i s l i n k e d t o prevent f a l s e a s s o c i a t i o n s and i s s t r u c t u r e d as f o l l o w s : ROUTE;SPECIES;ORDER;STUDY TYPE;VALUE; TOXIC EFFECTS ( i f any);SPECIFIC

EFFECT/ORGAN SYSTEM AFFECTED

An example of t h i s c a t e g o r i z a t i o n would be: ORAL;RAT ;RODENTS ;LD50; 54 MG/KG;TOXIC EFFECTS ;CARCINOGENIC Each term or phrase between semicolons i s d i r e c t l y s e a r c h able and can be ANDed together. For example, (IX)

ORAL AND RAT AND LD50 AND CARCINOGENIC

The i n f o r m a t i o n contained i n the f i e l d s t h a t are a s t e r i s k e d i n Table 1 are searchable as f r e e t e x t terms; t h a t i s , unique words which can be ANDed or ORed together. The (CT) f i e l d i d e n t i f i e r i s used when searching the Toxic Data Source f i e l d and (TW) i s used when searching f o r i n f o r m a t i o n i n the remaining "free text" f i e l d s . CHEMLINE-TOXLINE Search The previous d i s c u s s i o n s presented an overview of three of the N a t i o n a l L i b r a r y of Medicine's o n - l i n e f i l e s ; next w i l l be an examination of the v a r i o u s ways i n which CHEMLINE can be u t i l i z e d i n enhancing the chemical a c c e s s i b i l i t y t o t o x i c o l o g i c a l i n f o r m a t i o n i n another f i l e . Using the p e s t i c i d e , Leptophos, as an example, F i g u r e s 4 and 5 show how t h i s i s done.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

64

RETRIEVAL

NLM

O F MEDICINAL

BIOS IS

MEDLARS

SECT 1-5 62-64 59,60

PROFILES

ASHP

EPA PESTICIDES ABSTRACTS

BIOL. ABSTR. & BioRESEARCH INDEX

CHEMICAL ABSTRACTS

CHEMICAL

ORNL

INT. PHARM. ABSTRACTS

SPECIAL FILES

PROFILES

[ TOXBIB

J

(

CBAC

Figure 3.

INFORMATION

)

(

HEEP

( V

Λ J

PESTAB Λ ΗΛΡΑΒ J

Sources of TOXLINE

(

ΓΡΤ

V

3(

EMIC

)

ET'IC

)

bibliographic files

SS 1

/c?

USER: "FILE CHEMLINE PROG: YOU ARE NOW CONNECTED TO THE CHEMLINE F I L E . SS 1 / C ? USER: (SY) LEPTOPHOS PROS: SS ( 1 ) PST6 ( 1 ) SS 2 / C ? USER: "PRT RN,SY,LO PROG:

RN SY SY SY SY SY SY SY SY SY LO

Figure 4.

CHEMLINE search

synonym

o LO L

-

21609-90-5

- VCS 506 - VELSICOL VCS 506 - VELSICOL 505 - PHOSVEL - K62-105 - LEPTOPHOS - FOSVEL - NK 711 - ABAR - TOXLINE - MEDLARS - EPATSCALIST

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN E T A L .

CHEMLINE

65

Searching the synonym f i e l d of CHEMLINE f o r Leptophos r e t r i e v e s one r e c o r d . PRINTing the RN, SY and LO f i e l d s provides the CAS R e g i s t r y Number, other synonyms which are known for the compound and the source of a d d i t i o n a l i n f o r m a t i o n . As seen i n Figure 5, a s w i t c h i s made t o the TOXLINE f i l e and the g e n e r i c name f o r the p e s t i c i d e i s entered. In t h i s case, 160 records are r e t r i e v e d i n which the term Leptophos occurs i n the t i t l e , a b s t r a c t or keyword f i e l d s . In Search Statement 2, the CAS R e g i s t r y Number and a few of the synonymous terms from CHEMLINE are ORed (combined) as search parameters. This r e s u l t s i n the r e t r i e v a l of 257 records cont a i n i n g the d e s i r e d chemical substance. Thus, the CHEMLINE i n f o r m a t i o n e f f e c t i v e l y i n c r e a s e s the TOXLINE r e t r i e v a l by 97 r e c o r d s . Search Statement 3 i s designed t o s e l e c t those c i t a t i o n s published i n 1977 i n which both Leptophos and some v a r i a t i o n of the term nerve The t i t l e and source o c r i t e r i a are then PRINTed. N a t u r a l l y , Statement 3 i s not intended t o provide a comprehensive search f o r the b i o l o g i c a l concept s i n c e other terms such as CNS or n e u r o t o x i c i t y are not i n c l u d e d . However, the l i s t i n g of the output from t h i s search could a s s i s t the user i n s e l e c t i n g b i o m e d i c a l terms r e l e v a n t t o the scope of the search. CHEMLINE Substructure Searches The f o l l o w i n g s e c t i o n s are provided t o demonstrate s e v e r a l approaches t o s u b s t r u c t u r e searching i n CHEMLINE (3-6). F i g u r e 6 shows the s t r u c t u r a l diagram of Leptophos and the c h a r a c t e r i s t i c s of a substructure search query based on the chemical s t r u c t u r e of this insecticide. A l o g i c a l approach t o t h i s query would be t o search CHEMLINE for the given common name, PRINT the systematic chemical name and s e l e c t name fragments that correspond to the d e s i r e d subs t r u c t u r e . This i s i l l u s t r a t e d i n the f i r s t p o r t i o n of F i g u r e 7. The name fragment PH0SPH0N0THI0IC i s s e l e c t e d s i n c e i t i s the fundamental or one of the most s i g n i f i c a n t f e a t u r e s of the chemical substance. PHENYL, as a name fragment, would e x p l i c i t l y exclude any s u b s t i t u t i o n s on the r i n g (such as c h l o r o p h e n y l ) . This i s a requirment f o r Ring A as shown i n F i g u r e 6. The coord i n a t i o n of the two name fragments r e s u l t s i n the r e t r i e v a l of 34 r e c o r d s . The formula fragments CL and BR along w i t h the name fragment 4 r e q u i r e s t h a t a t l e a s t one c h l o r i n e and one bromine atom be present and the 4 - p o s i t i o n of a r i n g ( o r chain) be s u b s t i t u t e d . These requirements r e t r i e v e 294 records from CHEMLINE. The i n t e r s e c t i o n of those records r e t r i e v e d i n Search Statements 2 and 3 should s a t i s f y the c r i t e r i a e s t a b l i s h e d f o r the s u b s t r u c t u r e search (6 r e c o r d s ) .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

66

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

SS 2 /C? USER: " F I L E TOXLINE PROG: YOU ARE NOW CONNECTED TO THE TOXLINE F I L E . SS 1 / C ? USER: LEPTOPHOS PROG: SS ( 1 ) PSTG ( 1 6 0 ) SS 2 / C ? USER: 2 1 6 0 9 - 9 0 - 5 OR PHOSVEL OR FOSVEL OR LEPTOPHOS PROG: SS (2) PSTG ( 2 5 7 ) SS 3 / C ? USER: 2 AND ALL NERV: AND 77 (YP)

USER: "PRT 1 T I , SO PROG: 1 TI

Figure 5.

TOXLINE

- NEUROTOXICITY OF ORGANOPHOSPHORUS INSECTICIDES LEPTOPHOS AND EPN.

so - J ENVIRON SCI HEALTH ( Β ) ; VOL 12, iss

search

1 9 7 7 , P269-87

ο-ί-b* OCH3 LEPTOPHOS

SUBSTRUCTURE

CHARACTERISTICS: 1.

No SUBSTITUTION ON RING A

2.

ANY ESTER

3.

ONE OR MORE CHLORINE ATOMS ANYWHERE ON RING Β IN COMBINATION WITH A BROMINE ATOM ON THE ^-POSITION

Figure 6.

Characteristics of leptophos-related substructure search

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN E T A L .

67

CHEMLINE

USER: (SY) LEPTOPHOS PROG SS (1) PSTG (1) SS 2 /C? USER: "PRT N l PROG: 1 NI

- PHOSPHONOTHIOIC ACID, PHENYL-, 0-( I-BROMO-2,5-DICHLOROPHENYL) 0-METHYL ESTER (9CI) Î

SS 2 /C? USER: (NF) PHOSPHONOTHIOIC AND PHENYL PROG: SS (2) PSTG (34) SS 3 /C? USER: (FF) CL AND BR AND 4 PROG: SS (3) PSTG (294) SS 4 /C? USER: 2 AND 3 PROG: SS (4) PSTG (6) SS 5 /C? USER: "PRT Nl

Figure 7.

ÏLWimt

CHEMLINE

SIARCH_ÔMR£y^ PiLNT .AJMEY. (SI)

SI

CHEMICAL SUBST. PRIME NAME

(Nl)

Nl

CHEMICAL NAME FRAGMENTS

SOURCE

IDENTIFICATION

(NF)

--

CHEMICAL DEFINITION

•

CD

CAS REGISTRY NUMBER

(RN)

RN

MOLECULAR FORMULA

(MF)

MF

MOLECULAR FORMULA FRAGMENTS

(FF)

-

MOLECULAR WEIGHT

-

nw

WISWESSER LINE NOTATION

(WL)

WL

SYNONYMS

(SY)

SY

TOXICITY DATA INDEX STRINGS

(IX)

TDKW

so

TOXIC DATA SOURCE AQUATIC TOXICITY RATING

*

TOXICOLOGY & CANCER REVIEW

•

STANDARDS a REGULATIONS

*

NIOSH CRITERIA DOCUMENTS

•

NC

•

ST

STATUS

AQ TC Ç

R

TEXT WORDS

(TW)

--

CITATIONS TERMS

(CT)

so

• #

*

substructure search

SEARCHABLE AS TEXT WORDS SEARCHABLE AS CITATIONS TERMS

Table L

RTECS—Unit

Record Description

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

68

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

The systematic chemical names are then PRINTed to compare the search r e s u l t s w i t h the d e s i r e d s u b s t r u c t u r e query. The s t r u c t u r a l diagrams f o r the substances r e t r i e v e d are i l l u s t r a t e d i n F i g u r e s 8 and 9. CHEMLINE-RTECS Substructure Search The next example of a CHEMLINE s u b s t r u c t u r e search i s f o r c h l o r i n a t e d d i b e n z o d i o x i n s . As seen i n Figure 10, t h i s subs t r u c t u r e query i s d e r i v e d from the h e r b i c i d e contaminant D i o x i n . The search can be approached without u s i n g any chemical nomenclature through use of the Formula Fragment (FF) and r i n g informat i o n f i e l d s (Ring Elemental (RE) a n a l y s i s and Component Line (CL) formula). The search r e t r i e v e s f o r t y r e c o r d s ; a few of the chemical names are PRINTed t o review the output Since systematic chemica mula fragments are a l s CHEMLINE nomenclatural output to perform a s u b s t r u c t u r e search that i s c o r r e l a t e d w i t h a b i o l o g i c a l concept i n RTECS. T h i s would o b v i a t e the need t o c a r r y the chemical i d e n t i f i e r s f o r the f o r t y CHEMLINE records i n t o the RTECS f i l e . A f t e r accessing the RTECS f i l e (Figure 11), the name f r a g ments common t o each name l i s t e d i n the CHEMLINE search (DIBENZO and DIOXIN) and the formula fragment CL are used t o r e t r i e v e s i x records. The RTECS T o x i c i t y Data f i e l d s (IX) are then searched f o r the terms ORAL, RAT and TERATOGENIC and the records c o n t a i n ing these terms i n the index s t r i n g are i n t e r s e c t e d w i t h Search Statement 1 t o r e t r i e v e two records (Search Statement 2 ) . F i n a l l y , p a r t of the f i r s t RTECS record i s l i s t e d t o o b t a i n the t o x i c data f o r the c h l o r i n a t e d d i b e n z o d i o x i n . Summary This paper has d e s c r i b e d s e v e r a l approaches t o the u t i l i z a t i o n of an o n - l i n e chemical d i c t i o n a r y f i l e i n l i n k i n g chemical s t r u c t u r e s t o b i o l o g i c a l i n f o r m a t i o n . Through use of nomenclat u r a l , molecular formula and r i n g screens, the c a p a b i l i t y e x i s t s i n CHEMLINE t o e f f e c t i v e l y i d e n t i f y chemical substances w i t h s p e c i f i c s t r u c t u r a l c h a r a c t e r i s t i c s . Since CHEMLINE i s an i n t e g r a l p a r t of the N a t i o n a l L i b r a r y of Medicine's On-Line S e r v i c e s , i t i s then p o s s i b l e t o c o r r e l a t e the s u b s t r u c t u r a l data w i t h b i o l o g i c a l i n f o r m a t i o n and data contained i n b i b l i o g r a p h i c and/or data f i l e s e x i s t i n g w i t h i n the same computer environment.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

SPANN

E T AL.

1 NI

CHEMLINE

- PHOSPHONOTHIOIC ACID, PHENYL-,

0-(4-BROMO-2,5-DICHLOROPHENYL)

ESTER, POTASIUM SALT (9CI) Cl

2 NI

- PHOSPHONOTHIOIC ACID, PHENYL-, 0-(4-BROMO-2,5-DICHLOROPHENYL) 0-METHYL ESTER, MIXT, WITH 1,1'-(2,2,2-TRICHLOROETHYLIDENE)BIS( I-CHLOROBENZENE) (9CI) £

NI

- PHOSPHONOTHIOIC ACID, PHENYL-, 0-(4-BROMO-2-CHLOROPHENYL) 0-METHYL ESTER (9CI)

Figure 8.

Substructure search results

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

O F MEDICINAL

CHEMICAL

INFORMATION

PHOSPHONOTHIOIC ACID, PHENYL-, 0-(4-BROMO-2,5-DICHLOROPHENYL) 0-METHYL ESTER (9C1)

PHOSPHONOTHIOIC ACID, PHENYL-, 0-(4-BROMO-2,5-DICHLOROPHENYL) 0-ETHYL ESTER (9CI)

PHOSPHONOTHIOIC ACID, PHENYL-, 0-(4-BROMO-2,6-DICHLOROPHENYL) 0-METHYL ESTER (9CI)

Figure 9.

Substructure search results

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

5.

SPANN

71

CHEMLINE

E T AL.

DIOXIN

Cl

CHLORINATED DIBENZODIOXINS USER: (RE) C402-C6-C6 AND 0C20C2 (CL) AND CL (FF) PROG: SS iS) PSTG (40) SS 2 /C? USER: "PRT 4 NI PROG: 1 NI - DIBENZ0(B,E)(1,4)DI0XIN,

TETRACHLORO- (9CI)

2 NI - DIBENZ0(B,E)(1,4)DI0XIN,

1,2.3.7.8-PENTACHL0R0- (9CI)

3 NI - DIBENZ0(B,E)(1,4)DI0XIN,

1,2,3,4,6,7,8-HEPTACHLORO- (9CI)

4 NI - DIBENZ0(B,E)(1,4)DICXIN,

Figure 10.

HEXACHLORO- (9CI)

Chlorinated dibenzodioxins search

SS 2 /C?

USER: "FILE RTECS PROG: YOU

ARE NOW CONNECTED TO THE RTECS FILE.

SS 1 /C? USER: (NF) DIBENZO AND DIOXIN AND CL (FF) PROG: SS (1) PSTG (6) SS 2 /C? USER: (IX) ORAL AND RAT AND TERATOGENIC AND 1 PROG: SS (2) PSTG (2) SS 3 IV. USER: "PRT 1 TOXDATA PROG: SI

- NI0SH/HP32000

Nl

- DIBENZO-P-DIOXIN, HEXACHLORO-

RN

- 34465-46-8

SO

- ADCSAJ ADVANCES IN CHEMISTRY SERIES. 120,55,73

TDKW- ORAL;RAT;RODENTS;LDLo; 100 MG/KG

ORAL; RAT;RODENTS;TDLo;100

UG/KG/(6-15D

PREG)

; TOXIC EFFECTS

TERATOGENIC

Figure 11.

RTECS search

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

72

ABSTRACT The National Library of Medicine's (NLM) on-line chemical dictionary f i l e (CHEMLINE) is primarily used to enhance the retrieval of bibliographic information associated with chemical substances. This discussion demonstrates the utility of CHEMLINE as a mechanism to link chemical substructures to biological data. Search techniques are developed to integrate classes of structur ally related chemicals with toxicity data and information con tained in on-line retrieval files such as the Registry of Toxic Effects of Chemical Substances (RTECS) and TOXLINE. Acknowledgements The authors gratefull by Dr. Henry M. Kissman and Mrs. Joan H. Cepko of the Toxicology Information Program. Literature Cited 1.

2.

3.

4.

5.

6.

S c h u l t h e i s z , R. J., Kannan, K. L. and Walker, D. F., "Design and Implementation of an O n - l i n e Chemical D i c t i o n a r y (CHEMLINE)", J. Am. Soc. I n f . Sci., Accepted f o r p u b l i c a t i o n in Vol. 29 (1978). For s a l e by the Superintendent of Documents, U . S . Government Printing O f f i c e , Washington, D . C . 20402 GPO Stock No. 017-033-00271-1. F i s a n i c k , W., Mitchell, L. D., S c o t t , J.A., and Vanderstouw, G. G., "Substructure Searching of ComputerReadable Chemical A b s t r a c t s S e r v i c e N i n t h Collective Index Nomenclature Files", J. Chem. I n f . Comput. Sci., 15 (2) 73-84 (1975). Dunn, R. G., F i s a n i c k , W., and Zamora, Α . , " A Chemical Substructure Search System Based on Chemical A b s t r a c t s Index Nomenclature", J. Chem. I n f . Computer. Sci., 17 ( 4 ) , 212-219 (1977). "Substructure Searching of Computer-Readable CAS 9CI Chemical Nomenclature Files (Based on Nomenclature in the N i n t h Collective Index of Chemical A b s t r a c t s ) (1972-1976)", Chemical A b s t r a c t s S e r v i c e , Columbus, Ohio, Aug. 1974, 128 p p . , ISBN 8412-0204-4, LCN 74-14778. V a s t a , B . M . and Spann, M. L., "Chemical Searching C a p a b i l i t i e s of CHEMLINE", presented at the 172nd N a t i o n a l Meeting of the American Chemical S o c i e t y , August, 1976.

RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

6

C h e m i c a l a n d Biological Data—an Integrated

On-Line

Approach

Ε. E. TOWNSLEY and W. A. WARR Data Services Group, ICI Pharmaceuticals Division, PO Box 25, Alderley Park (Mereside), Macclesfield, Cheshire, SK10 4TG, England For some years CROSSBO technolog (1-5) ha bee d b ICI Pharmaceuticals Division database. A computerised system f o r biological c o n t r o l and f o r the storage and retrieval of biological data has a l s o been i n o p e r a t i o n for many y e a r s . However, the biological database was h e l d separately from the chemical database and there were some i n t e r f a c e problems. The advantage of the new i n t e g r a t e d chemical and biological system over the previous two separate systems i s the ease of access ( i n c l u d i n g o n - l i n e access) to all i n f o r m a t i o n , both biological and c h e m i c a l . In the past it was not q u i t e so easy, for example, to f o l l o w a biological search w i t h a search of the chemical database, or v i c e v e r s a . When the Division installed a Burroughs 6700 computer i t was necessary to redesign the databases and convert all programs which had earlier run on a Burroughs 4700 machine. I t was decided that development, improvement and conversion should be undertaken at the same time, and an i n t e g r a t e d o n - l i n e database is now in use. This ever-expanding database at present holds 190,000 chemical compounds from f i v e ICI divisions: data on 267 distinct biological t e s t s : and over 1,000,000 biological test results from Pharmaceuticals Division. Linked to the computer are three Burroughs t e r m i n a l computers and eight v i s u a l d i s p l a y units. The system's uses are chemical and biological data registration and retrieval, and biological c o n t r o l . The b i o l o g i c a l c o n t r o l system manages the processing of samples submitted for b i o l o g i c a l assay. Data Services Group takes a compound from the chemist, weighs appropriate samples for a l l the necessary b i o l o g i c a l t e s t s and c o l l e c t s t e s t r e s u l t s from the b i o l o g i s t s . The register allocate example, 01 where

f i r s t step i n the b i o l o g i c a l c o n t r o l sequence i s to the s t r u c t u r e of a compound, and i f i t i s n o v e l , to i t the next a v a i l a b l e s i x - f i g u r e M number, say, f o r ΜΙΟΟ,ΟΟΟ. This f i r s t sample i s r e f e r r e d to as M100000/ 01 i s c a l l e d a stroke number. I f the compound i s not 0-8412-0465-9/78/47-084-073$05.00 Published 1978 American Chemical Society

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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n o v e l , the sample w i l l be a l l o c a t e d the next a v a i l a b l e s t r o k e number t o the p r e v i o u s l y a l l o c a t e d M number, e.g. M80996/09. The next step i s to r e g i s t e r the property data (see F i g u r e 1) of the given sample and t o a l l o c a t e a sample storage number, which i s the s h e l f storage number f o r the stock b o t t l e . The handling codes recorded on the property f i l e are twol e t t e r codes i n d i c a t i n g whether any unusual h a n d l i n g precautions need to be observed (e.g. TX f o r " t o x i c " , KC f o r "keep c o l d " ) . I n t e n t i o n - t o - t e s t data i s held on a dynamic f i l e whose record layout i s shown i n F i g u r e 2. For each sample/test combination an i n t e n t i o n - t o - t e s t record i s created and used t o manage the progress of the sample from the chemist's i n i t i a l submission through to the c o l l e c t i o n of t e s t r e s u l t s from the b i o l o g i s t , a f t e r whic removed. Most of the data i n F i g u r e 2 i s s e l f - e x p l a n a t o r y . A t e s t i s represented by two or three characters (e.g. AB o r AB3 f o r a n t i b a c t e r i a l t e s t s ) f o r e x t e r n a l use and a number f o r machine use. The sample property r e c o r d must be created before an i n t e n t i o n - t o - t e s t record can be made because data needed f o r the l a t t e r record i s a b s t r a c t e d from the former (compare F i g u r e s 1 and 2 ) . The a l l o c a t i o n of a p r i o r i t y i s important because i t ensures that compounds are progressed through the system i n such a way that important p r o j e c t compounds are always s e l e c t e d i n preference to non-project compounds where there are more t e s t submissions than a b i o l o g i s t can cope w i t h at any one time. Four p r i o r i t i e s are used. Compounds made by the chemist f o r t e s t i n g i n connection w i t h h i s own p r o j e c t are given p r i o r i t y 1 (the h i g h e s t ) . The chemist may e l e c t to send the same compound f o r t e s t s unconnected w i t h h i s p r o j e c t and the i n t e n t i o n - t o - t e s t records f o r these w i l l have p r i o r i t y 2. Compounds the chemist has s e l e c t e d by means of a s u b s t r u c t u r e search around a " l e a d " compound, w i l l be t e s t e d on p r i o r i t y 3 and screening compounds randomly s e l e c t e d by Data Services Group are tested under p r i o r i t y 4 (the l o w e s t ) . The date of submission i s recorded so t h a t , f o r a given p r i o r i t y , records created e a r l i e r are processed before those created l a t e r . The s t a t u s of a sample i s described i n F i g u r e 3. When an i n t e n t i o n - t o - t e s t record i s created i t has the s t a t u s value s e t to 1. This value i s updated stepwise from 1 to 6 as the sample progresses through the weighing and documentation process, followed by submission to the b i o l o g i s t and f i n a l l y reaches the r e s u l t c o l l e c t i o n and n o t i f i c a t i o n stage. When the t e s t c o n t r o l f u n c t i o n f o r the sample i s complete, the i n t e n t i o n record i s removed from the f i l e .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

TOWNSLEY

A N D WARR

Chemical

and Biological

Data

M number/stroke number Key: Index s e q u e n t i a l Company r e g i s t r y number S u f f i x p o i n t e r (e.g. 0201 o r 0001 i n Figure 7) Sample a v a i l a b l e / n o t a v a i l a b l e / r e s e r v e d Sample storage number Chemist's i n i t i a l s and notebook reference S a l t data S o l u b i l i t y codes Handling codes Figure 1.

Property file (standard data set)

M number Stroke number Key Test number Priority Key Date 0 Status Test l e t t e r s Sample storage number Chemist's i n i t i a l s and s e c t i o n Handling codes Figure 2.

Status 1 2 3 4 5 6

Index s e q u e n t i a l Index s e q u e n t i a l

Intention-to-test file (standard data set)

Meaning Sample f o r t h i s t e s t unweighed and undocumented. Sample f o r t h i s t e s t weighed but undocumented. Sample f o r t h i s t e s t weighed and documented. Sample f o r t h i s t e s t submitted t o b i o l o g i s t . Test r e s u l t has been received from b i o l o g i s t . Test r e s u l t n o t i f i e d t o s e c t i o n leader and i n t e n t i o n - t o - t e s t record ready f o r removal. Figure 3.

Status of sample on intention-to-test file

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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From the i n t e n t i o n - t o - t e s t f i l e i s generated a m a t r i x report which d e t a i l s the c u r r e n t s t a t e of sample p r o g r e s s i o n against t e s t . I t r e p o r t s the numbers of samples f o r each t e s t at each management l e v e l , up t o and i n c l u d i n g s t a t u s f o u r , subdivided by p r i o r i t y . Enquiry r o u t i n e s give more d e t a i l e d i n f o r m a t i o n at the s p e c i f i c sample l e v e l . B i o l o g i c a l t e s t s are of two types - c u r r e n t and screen. A current t e s t i s one which r e q u i r e s p r o j e c t compounds to pass as q u i c k l y as p o s s i b l e from chemist to b i o l o g i s t , and such compounds must be weighed and documented immediately a f t e r i n p u t . U s u a l l y there i s only a small number of samples to be processed each week f o r one of these t e s t s . A screen t e s t i s one which r e q u i r e s a r e g u l a r supply of a f i x e d number of sample made up of chemist's p r o j e c submitted compounds, and the balance i s provided from p r i o r i t y 3 and 4 submissions. To c a t e r f o r the two types of t e s t there are two ways i n which samples are s e l e c t e d f o r progress to weighed and documented s t a t u s and then t o submission t o the b i o l o g i s t . The f i r s t produces weighing i n s t r u c t i o n s , b o t t l e l a b e l s and t e s t documentation f o r samples s e l e c t e d by M number e s s e n t i a l l y current p r o j e c t compounds. U s u a l l y , a l l the t e s t samples from one stock b o t t l e are weighed at the same time, i r r e s p e c t i v e of t e s t type, so as to minimise b o t t l e h a n d l i n g . However, documentation f o r screen t e s t s i s produced a t a l a t e r stage. Thus the s t a t u s of c u r r e n t t e s t records i s updated to 3 and that of screen t e s t records t o 2, by t h i s "weighing r o u t i n e " . The second weighing r o u t i n e , which i s geared to screen t e s t requirements, s e l e c t s s t a t u s 1 and 2 records by t e s t . F o r each t e s t the samples are s e l e c t e d i n p r i o r i t y o r d e r , and w i t h i n p r i o r i t y , by date. Again, weighing i n s t r u c t i o n s and b o t t l e l a b e l s (where needed) and t e s t documentation are produced together w i t h two d i f f e r e n t working documents which d e t a i l sample numbers and r e l a t e d d a t a , one f o r the b i o l o g i s t ' s use and one to be used w i t h i n Data Services Group. A t e s t d e t a i l s f i l e i s maintained which holds constant data p e r t a i n i n g to each t e s t , as shown i n F i g u r e 4. When t e s t r e s u l t data i s returned i t i s v a l i d a t e d against the d e t a i l s h e l d on t h i s f i l e . At the same time as an i n t e n t i o n - t o - t e s t r e c o r d i s c r e a t e d , a " r e s u l t " entry i s created on the summary r e s u l t f i l e (see F i g u r e 5) w i t h the r e s u l t area l e f t blank. As the sample progresses to submitted s t a t u s the blanks are r e p l a c e d by "S". F i n a l l y t h i s area w i l l be occupied by the b i o l o g i s t ' s summary

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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77

t e s t r e s u l t s (e.g. A f o r a c t i v e o r I f o r i n t e r e s t i n g ) f o r up t o four s u b d i v i s i o n s of h i s t e s t . A screen f i l e (Figure 6) i s maintained a t the compound l e v e l as opposed to the sample l e v e l . Each compound i s a l l o c a t e d a sample a v a i l a b i l i t y b i t and one b i t per t e s t which i s used to i n d i c a t e whether or not any sample of the compound has been submitted f o r that t e s t . This f i l e i s maintained because the summary t e s t r e s u l t f i l e i s very l a r g e and before i t i s searched for t e s t r e s u l t i n f o r m a t i o n the screen f i l e i s q u i c k l y scanned so as to reduce the number of accesses that need be made t o the larger f i l e . To r e t u r n t o the beginning of the r e g i s t r a t i o n process, a chemical s t r u c t u r e i s input as a molecular formula and a Wiswesser L i n e N o t a t i o n (WLN) (6-7) The f i r s t o n - l i n e r o u t i n e generates a molecular formul agrees w i t h the input c a r r i e d out a g a i n s t the WLNs already on f i l e . I f the compound i s novel i t s WLN i s r e g i s t e r e d and a fragment screen i s generated from the n o t a t i o n and stored (separate from the WLN) on a d i r e c t data s e t w i t h the company r e g i s t r y number (CR number) as key. There are 148 designated fragments, the presence of which are i n d i c a t e d by b i t s s e t to one r a t h e r than zero. Each fragment i s r e l a t e d t o a s i n g l e WLN c h a r a c t e r , o r a group o f them, o r t o a f e a t u r e of a WLN c i t e d r i n g . Ring s u b s t i t u e n t fragments are d i f f e r e n t i a t e d from s i m i l a r fragments in a chain. The way WLN data i s held i s shown i n Figure 7. I t can be seen from t h i s that a CR number represents a WLN, or a twodimensional s t r u c t u r e whereas a d i v i s i o n a l reference number (e.g. an M number) represents a compound. Sometimes i n f o r m a t i o n such as stereochemistry, has to be s u f f i x e d t o the WLN proper to give a f u l l r e p r e s e n t a t i o n of a compound. I n the many cases where there i s no s u f f i x , CR number and d i v i s i o n a l reference number are e q u i v a l e n t . The combination of WLN-last-16-inverted plus WLN length was chosen as key because f o r a very high p r o p o r t i o n of the records on the f i l e t h i s key i s unique. The mean length of n o t a t i o n s r e g i s t e r e d on the database i s 21 c h a r a c t e r s . The main WLN f i l e holds up t o 34 characters o f n o t a t i o n . A s m a l l number of WLNs (about 7%) have t o overflow onto a s u b s i d i a r y f i l e . T h i r t y - f o u r characters of WLN are held on the main f i l e , because that number reduces wasted space on the main and overflow f i l e s t o a minimum. The database i s designed so t h a t i t may be accessed by WLN, d i v i s i o n a l reference number, CR number or molecular formula.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Test number Key 1 - d i r e c t Test l e t t e r s Key 2 - index s e q u e n t i a l F l a g - i s t e s t current o r screen? Biologist's i n i t i a l s Weight of sample r e q u i r e d f o r t e s t Stationery Test r e s u l Figure 4.

Test detaih file (direct data set)

Key - index s e q u e n t i a l M number/stroke number/record number Test l e t t e r s - p r i o r i t y ^) occurs once f o r each date t e s t on t h i s sample chemist summary r e s u l t

Figure 5.

Summary result file (standard data set)

M number Key - d i r e c t F l a g - sample a v a i l a b l e / n o t a v a i l a b l e Tested/untested b i t s f o r 480 p o s s i b l e t e s t s Figure 6.

Screen file (direct data set)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Biological

Data

79

There i s a separate data s e t f o r compounds which cannot be coded i n t o WLN (e.g. seed e x t r a c t s and r e a c t i o n products of unknown s t r u c t u r e ) and these are s t o r e d on a random data s e t w i t h d i v i s i o n a l r e f e r e n c e number as key. The CROSSBOW chemical search system (1-5) i s a m u l t i l e v e l one. Search of the b i t screens i s f i r s t c a r r i e d out and t h i s q u i c k l y and cheaply reduces the f i l e to ten per cent (or l e s s ) of i t s o r i g i n a l s i z e . There w i l l almost c e r t a i n l y be many f a l s e drops but most of these can u s u a l l y be removed by s t r i n g search of the WLNs and/or molecular formulae and/or reference numbers. S t r i n g searching i s slower and more expensive than b i t search. Connection t a b l e generation and atom-by-atom search of the connection t a b l e s (the t h i r d search l e v e l ) are s t i l l slower and even more expensive, but the atom-by-atom search program i s a very powerful t o o l which i d i about 80% f a l l searches. The CROSSBO any search are f i n a l l y inpu display program. B i t and s t r i n g searching i s an i n t e r a c t i v e process. The paramaters are input on a VDU, the h i t count i s d i s p l a y e d o n - l i n e and, i f necessary, the search parameters can be modified and the search repeated. At the end of a s e s s i o n , search h i t f i l e s are merged as r e q u i r e d and connection t a b l e generation, atom-byatom search and s t r u c t u r e d i s p l a y are run batchwise. An average b i t and s t r i n g search takes about f i v e minutes (searching 190,000 compounds). The CROSSBOW connection t a b l e generation program handles 1500-2000 compounds a minute, and the atom-by-atom program searches 600 compounds a minute. Well over 90% of n o t a t i o n s are amenable to connection t a b l e generation and over 90% of the compounds on the database can be s t r u c t u r a l l y d i s p l a y e d d i r e c t l y from the connection t a b l e . (The remainder are held on the database i n a f i l e of " d i f f i c u l t " structures.) A b i t search i s s p e c i f i e d u s i n g combinations of AND, OR and NOT l o g i c , and a l s o nested AND-within-OR l o g i c , as r e q u i r e d . S t r i n g search allows the same l o g i c a l o p e r a t o r s , but i n a d d i t i o n there are ignore and followed-by f a c i l i t i e s and other s p e c i a l i s e d syntax t o s i m p l i f y the s p e c i f i c a t i o n of s e v e r a l alternative strings. F i g u r e 8 shows a t y p i c a l b i t and s t r i n g search. I n the b i t s search, fragments 50 and 137 must both be present. Neither fragment 134 nor fragment 135 may be present, and nor may be fragment 136. The OR clause s t a t e s that i f the combination of ( e i t h e r 17 or 18) and ( e i t h e r 71 or 72) i s not present, then, a l t e r n a t i v e l y the combination of ( e i t h e r 67 o r 68) and ( e i t h e r 28 or 29) must be present. The Wiswesser s t r i n g s which could represent t h i s s u b s t r u c t u r e a r e :

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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M number nnnnnn represents (WLN+suffix) Λ CR number NNNNNN represents WLN k

Λ

,

T66 BOT&J C3Y1&3Y1&3Y1&1 C l G l HQ I I J l &&DL FORM Overflow record NNNNNN/0001

Overflow record NNNNNN/0201

WLN F i l e Record (Direct Data Set) NNNNNN

CR number.

Key - d i r e c t .

1J I I QH 1G 1C 1 WLN l e n g t h . 0039 T66 B0T&J...G1 HQ

Up t o 34 characters of WLN.

C29H5002

M o l e c u l a r formula. + Various d i v i s i o n a l references and f l a g s . Figure 7.

Key - index random.

Storage of chemical structural information

X = 0CH or NHR (R^H) 3

Only the one r i n g present.

Hal Subst halogen One benzene r i n g Subst CO.O Subst CO Chain methyl Chain NH Ring systems

50 137 71 67 17 28 134

72 68 18 29 135 136

Parameters AND,BITS "50 137". Ν 0 Τ , /134 135 136/. 0R,/71 72/ /17 18/,/67 68/ /8 29/. %*#V##0M#.END 0R,WLN -l/l-"10VR ,"MVR , ff

M

Figure 8.

fl

Bit and string search

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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81

Notations beginning "10VR" or n o t a t i o n s c o n t a i n i n g "MVR" or n o t a t i o n s c o n t a i n i n g xVO" or " xVM" 11

where χ = any character but space (represented by % i n Figure 8). The l a s t two s t r i n g s are combined together, the hash marks e n c l o s i n g c h a r a c t e r s which are a l t e r n a t i v e s . Atom-by-atom search i s r e s o r t e d to i f the s t r i n g search of WLNs and/or molecular formulae and/or reference numbers i s not s p e c i f i c enough. This w i l l occur i f , f o r example, the s u b s t r u c t u r e i s very branched or may be p a r t i a l l y o r wholly embedded i n a r i n g . An atom-by-atom search may a l s o be needed i f there i s a s p e c i f i c p o s i t i o n a l r e l a t i o n s h i p between two groups and t h a t r e l a t i o n s h i by WLN s u b - s t r i n g s . Th l a s t category. An atom-by-atom search t o f i x the s p a t i a l r e l a t i o n s h i p between the halogen and the carbonyl groups i s shown i n F i g u r e 9. E, F, G, I , D, T, U, 0, Q and M are the p o s s i b l e ways the nodes 1-7 could be represented i n the CROSSBOW connection t a b l e , a node being an atom and i t s surrounding bonds. NOTR stands f o r "not i n a r i n g " and RINGSA f o r a s i n g l e benzene r i n g (S) of the type shown i n the RINGSCREENA parameter. The RINGSCREENA parameter designates a benzene r i n g which has s u b s t i t u e n t s a t the 1 and 3 p o s i t i o n s and o p t i o n a l l y s u b s t i t u e n t s a t other p o s i t i o n s a l s o . The seventh node must not be t e r m i n a l (or the Q would represent OH o r the M, NH2) so the L before the QM i n d i c a t e s t h a t t h i s node must be l i n k i n g . The network parameter B65X, i n d i c a t e s that the seventh node i s attached t o the f i f t h . I f d e s i r e d , a b i o l o g i c a l search may be c a r r i e d out before or a f t e r the chemical search. This may perform the f u n c t i o n of reducing the t o t a l search output, or i t may be c a r r i e d out merely t o produce a l l the t e s t and sample data f o r each compound which i s a h i t on the chemical search. The operator MNOS i s used t o s p e c i f y the range of numbers to be searched and, i f r e q u i r e d , to l i m i t the number of h i t s . The operator OUT i s used t o s p e c i f y what sample and r e s u l t data i s to be p r i n t e d f o r each h i t . The operators EVER and NEVER ( s i m i l a r to OR and NOT) are used t o search the data on the property f i l e and the summary r e s u l t f i l e , u s i n g the screen f i l e , i f r e l e v a n t , as a p r e l i m i n a r y screen. Thus, f o r example, one may search f o r a l l the a c t i v e a n t h e l m i n t i c s Dr Robinson made and reserved i n 1977; or a l l the s o l i d s i n l a r g e s i z e b o t t l e s which are a c t i v e i n an a n t h e l m i n t i c t e s t but have not been t e s t e d i n any of the l i v e r f l u k e t e s t s .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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= NH or 0.

Parameters RINGSCREENASTCTCCC 1N0TR EFGI 2RINGSA Τ 3RINGSA DT 4RINGSA Τ 5N0TR TU 6N0TR 0 7N0TR LQM B65X Figure 9.

Atom-by-atom search

AA MNOS,1-20000=1000. EVER, (ACTIVE AB2 ) (AVAIL) . NEVER,(TESTED"AB3 ). OUT,BSLONG BRLONG ALL.END ,f

!!

n

Figure 10.

Biological search input

AA 13/03/78 *123456 MOLECULAR FORMULA C9H1003 WISWESSER NOTATION QYR&V01

SEARCH OUTPUT

HO--CH-//

I

L FORM

Ml31833

S

\.„/

C0-0-CH3

OTHER REF NUMBERS R12345 STROKE TEST NUMBER LETTERS 01

LFl

RESULT Ν

WEEK YEAR 48

Figure 11.

77

CHEM. WAW

SECT. PRIORITY 99

2

Search output

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

6.

TOWNSLEY AND WARR

Chemical and Biological Data

83

F i g u r e 10 shows a b i o l o g i c a l search f o r 1000 compounds i n the range Ml to M20000, these compounds being a c t i v e i n the AB2 t e s t , having samples a v a i l a b l e and having never been t e s t e d i n the AB3 t e s t . The OUT parameter s t a t e s that f u l l sample data must be output and f u l l r e s u l t d e t a i l s f o r every t e s t to which each compound has been submitted. The output from a chemical search i s 8" χ 5" c a r d s , each card bearing a s t r u c t u r e drawn from the connection t a b l e by the computer. An example (not r e l a t e d to the two searches above) i s shown i n F i g u r e 11. Planned Developments Wiswesser L i n e N o t a t i o n i s l i k e l y to be used at ICI Pharmaceuticals D i v i s i o n f o r many years to come, not l e a s t because of i t s use i n commercial database bought b I C I f o example the Index Chemicu We are u n l i k e l y to put t h i s vast database o n - l i n e , although we r e g u l a r l y manipulate i t and search i t u s i n g the CROSSBOW system. We do, however, have immediate plans to augment our o n - l i n e database by adding v a r i o u s sample property and t e s t r e s u l t f i l e s for two more ICI d i v i s i o n s , and by adding the Commercially A v a i l a b l e Organic Chemicals Index (CAOCI) being b u i l t up by a number of European companies. Acknowledgement We would l i k e to express our thanks to Paul Bowler (who was instrumental i n the design of the database) f o r h i s h e l p f u l reading and c r i t i c i s m of t h i s paper. Literature Cited 1.

Hyde, E., Matthews, F . W . , Thomson, L.H. and Wiswesser, W . J . - "Conversion of Wiswesser N o t a t i o n to a C o n n e c t i v i t y M a t r i x f o r Organic Compounds". J.Chem.Doc., V.7 ( 4 ) , p.200-204 (1967).

2.

Thomson, L.H., Hyde, E . and Matthews, F.W. - "Organic Search and D i s p l a y Using a C o n n e c t i v i t y M a t r i x Derived from the Wiswesser N o t a t i o n " . J.Chem.Doc., V.7 (4), p.204-207 (1967).

3.

Hyde, E . and Thomson, L.H. - " S t r u c t u r e D i s p l a y " . J.Chem.Doc., V . 8 , p.138-146, 1968.

4.

E a k i n , D . R . - "The ICI CROSSBOW System" and Ash, J.E. "Connection Tables and Their Role in a System" i n Ash, J . E . and Hyde, E. - "Chemical Information Systems". Horwood, 1975.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

84

5·

E a k i n , D . R . , Hyde, E . and Palmer, G. - "The Use of Computers w i t h Chemical S t r u c t u r a l Information: ICI CROSSBOW System". P e s t i c i d e Sci. p.319-326, 1973.

6.

Smith, E . G . and Baker, P . A . - "The Wiswesser Line-Formula Chemical N o t a t i o n (WLN)". 3rd edition, CIMI, New J e r s e y , 1975.

7.

Baker, P . Α . , N i c h o l s , P.W.L. and Palmer, G. - "The Wiswesser Line-Formula N o t a t i o n " in "Chemical Information Systems" (loc.cit. at 4 ) .

8.

ICRS

® tapes c o n t a i n data from Current Abstracts of

Chemistry and Index Chemicus™ and both are a v a i l a b l e from the I n s t i t u t Chestnut S t r e e t RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7

U s e of P r o p r i e t a r y B i o l o g i c a l a n d C h e m i c a l Merck

D a t a at

& Co., I n c .

I. M. R. EGGERS, W. B. GALL, F. A. CUTLER, JR., and H. D. BROWN Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065

L i k e other pharmaceutica Dohme Research Laboratorie proprietary biological and chemical data. Moreover, the scientific s t a f f at MSDRL is using these data in i n c r e a s i n g l y s o p h i s t i c a t e d ways in their search f o r products to improve human and animal h e a l t h . An o u t l i n e of the systems (shown in F i g u r e 1) will be h e l p ful f o r understanding t h i s usage. Biological Data Biodata Systems S t r u c t u r e . The beginning of the biological data system grew out of the n o t i o n that it would be helpful to have all the data on a given compound immediately a v a i l a b l e in a single listing. From the original hand-posted card file, a punched card record was developed, using the concept of one record f o r one test. I n 1968 a computer tape record was s t a r t e d . This computer-stored file now c o n s i s t s of 2.5 million records i n s e v e r a l hundred t e s t s representing 135,000 compounds. The b a s i c record as it appears f o r entry i n t o computer storage is o u t l i n e d in Figure 2. Each record answers the f o l l o w i n g q u e s t i o n s , e i t h e r by summarizing the experiment i t s e l f or by l i n k i n g or p o i n t i n g to other f i l e s . 1.

When was the t e s t done?

2.

What was being tested? The 1 1 - d i g i t L-number i s the l i n k to the Chemdata f i l e s which w i l l supply the chemical name and, i f d e s i r e d , the s t r u c t u r e .

3.

How was the t e s t performed? The 4 - d i g i t t e s t number p r o v i d e s the l i n k to the f i l e of d e s c r i p t i o n s of the s e v e r a l hundred t e s t s c u r r e n t l y i n computer s t o r a g e . V a r i a t i o n s on the b a s i c t e s t , such as d i f f e r e n t routes of a d m i n i s t r a t i o n 0-8412-0465-9/78/47-084-085$05.50 Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

86

O F MEDICINAL

CHEMICAL

INFORMATION

B i o l o g i c a l Data Biodata Systems S t r u c t u r e Records A c q u i s i t i o n Search S t r a t e g i e s and Examples Chemical Data Chemical S t r u c t u r e Information Systems (CSIS) Chemical Name Compound R e p o s i t o r Transaction F i l e Chemdata Enhancements Transaction File/Inventory Interaction Figure 1.

1-•6 7-•8 9 10-•11 12-•15 16-•40 41-43 44-•72 73 74 75-•80

L-Number S a l t Form Check L e t t e r Batch Test Number Test Name P r o t o c o l Code Test R e s u l t Response Code Dose Code Test Date Figure 2.

Outline

Must be present and numeric Must be present and numeric Must pass program which checks c o l s . 1-8 Must be numeric , i f present Must be present and numeric Free Form Must be present and numeric Free Form Must be present and numeric Must be numeric , i f present Must be present - month, day, year

Basic record—biological

data

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

87

of t e s t compound, o r dosing schedules, are defined by the 3 - d i g i t p r o t o c o l codes. At present, the number of v a r i a t i o n s i s i n excess of 2,400. D e f i n i t i o n s are on each Data Sheet, very abbreviated. 4.

Why do we run t h i s t e s t ? The r a t i o n a l e i s a part of the p r o t o c o l , which i s w r i t t e n i n d e t a i l , dated, and signed by the b i o l o g i s t i n charge of the t e s t , and i s f i l e d i n the Biodata Department.

5.

Where was the t e s t done and who d i d i t ? These items are noted on the Data Sheet, as w e l l as being i n c o r p o r a t e d i n the P r o t o c o l write-up.

There are 53 column c a l l e d " f r e form" whos content v a r i e s w i t h the t e s t e s t i s described Biologica (se F i g u r 3). When p r o p e r l y f i l l e d out, these forms c o n s t i t u t e the set of d i r e c t i o n s f o r the keypunch operators. These are made out by the Biodata Department i n cooperation w i t h the b i o l o g i s t r e s p o n s i b l e f o r the t e s t and the chemist r e s p o n s i b l e f o r s u p p l y i n g m a t e r i a l s to the t e s t . These " f r e e form" items make the system b a s i c a l l y open ended. Among the parameters entered i n t o these " f r e e form f i e l d s " are those l i s t e d i n F i g u r e 4. The dose u n i t s may be e x p l i c i t , abbreviated, or implied. O c c a s i o n a l l y , the number of parameters to be recorded i s so l a r g e that the a c t u a l record i s simply a s e r i e s of numbers. I f necessary, two or more records are generated. A l l of these records c o n s t i t u t e d a t a , as opposed t o documents, and t h i s d i f f e r e n c e i s most s i g n i f i c a n t . The P r o t o c o l f i l e i s a document f i l e . I n the planning stage i s a Term Index to the p r o t o c o l f i l e , c o n t a i n i n g i n a searchable form such items as s p e c i e s , r o u t e of a d m i n i s t r a t i o n , whether enzyme, v i r u s , yeast, o r other type of t e s t , date of f i r s t record i n computer storage, name of i n v e s t i g a t o r , dose u n i t s , and p o s s i b l y others. Various other f i l e s are maintained f o r such purposes as housekeeping, a n a l y s i s of a c t i v i t i e s , and cross reference (see Figure 5). A l s o , there are some manually-posted f i l e s of b i o l o g i c a l data which predate the computer system. That i s the s t r u c t u r e of the system. Data must be acquired to b u i l d i t i n the f i r s t p l a c e and then to maintain i t on a current b a s i s . Records A c q u i s i t i o n . Records may be sent to Biodata from any Merck l a b o r a t o r y s i t e o r o u t s i d e i n v e s t i g a t o r . These may be i n the form o f : (1) copies of l a b o r a t o r y notebook records (the most common), (2) punched cards from systems not compatible w i t h

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

BER

NUM.

TEST

BIOLOGIST AND/OR CHEMIST

nun iiiniiiiiniiiiiii

EXPANDED TEST TITLE (100 CHARACTER MAXIMUM)

LU

BIOLOGICAL D A T A SHEET

DATE COLUMNS

75-7* 77-7· 7*40

oro«$

SL C O . , I N C .

N l w j I M t r

I PROTOCOL CODES:

DOSE CODES: COL. 74

RESPONSE CODES: COL. 73

MAHWAV

M E R C K 00 00

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

89

ours, (3) documents already d i s t r i b u t e d t o the a p p r o p r i a t e members of the s c i e n t i f i c s t a f f , (4) magnetic tapes, o r (5) manual card f i l e s . We g e n e r a l l y accept b i o l o g i c a l data i n whatever form i s most convenient and ask that no one do any e x t r a work beyond making copies. Approximately 96 percent of the keypunching f o r entry t o the computer i s done w i t h i n the Biodata Department. Documents are u s u a l l y not s u p p l i e d w i t h card column headings. The data entry personnel are expected t o use a f a i r degree of judgment i n reading documents from which data are to be keyed. They are able t o convert from one dosage u n i t t o another, t o c a l c u l a t e percentages based on c o n t r o l v a l u e s , t o recognize v a r i o u s types of e r r o r s and omissions, and to use many other s k i l l s o b v i o u s l y w e l l above the l e v e l of the average keypunch operator. They a l s o type, take d i c t a t i o n , operate e l e c t r o n i c data p r o c e s s i n g equipment, use microform and sometimes w r i t e compute elementary nature. Some data a r r i v e at the department already on punched cards or a magnetic tape. I n t h i s case, the conversion t o the des c r i b e d format, p l u s the t r a n s f e r i n t o the master computer f i l e i s handled by members of the Biodata s t a f f . Each computer-stored record has l i n k s t o the input which produced i t . The date and t e s t number are the primary l i n k s , but, t o the extent p o s s i b l e , experiment number and/or notebook and page number are a l s o recorded. The t e s t number p l u s the p r o t o c o l code serve to reference the f i l e of p r o t o c o l s . An e l a b o r a t e a u d i t t r a i l i s kept f o r changes which need to be made i n records. A l l accessory f i l e s are created w i t h i n the department. Data are input i n t o computer storage on a d a i l y b a s i s i n batch mode, and a l l data are a c c e s s i b l e as soon as entered. This d a i l y input creates a monthly f i l e , which seldom runs over 30,000 records. At the end of each month, i t i s merged i n t o the total f i l e . The f i l e has been defined and the data records have been acquired. The next s e c t i o n deals w i t h how they are used. Search S t r a t e g i e s and Examples. We have the c a p a b i l i t y of (a) s e l e c t i n g a group of data records such as those keyed by the same compound number, t e s t number, date, combinations t h e r e o f , or other c o n d i t i o n s , (b) comparing those records according t o some defined c o n s t r a i n t s and l o g i c , and (c) using the r e s u l t i n g a n a l y s i s to r e t r i e v e f o r p r i n t i n g the a p p r o p r i a t e records from the same or other f i l e s . I n complex s i t u a t i o n s , p r e v i o u s l y w r i t t e n programs a s s i s t the process. The queries d i r e c t e d t o Biodata f a l l f a i r l y n e a t l y i n t o e i g h t c a t e g o r i e s (see F i g u r e 6). U s u a l l y some i n t e r f a c e w i t h one or more of the Chemdata f i l e s i s necessary. The connecting l i n k i s the i d e n t i f i c a t i o n number of the m a t e r i a l , the L-number.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

90

RETRIEVAL

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I t i s important that the question be phrased so that i t i s completely unambiguous. We l i k e to negotiate each search i n d i v i d u a l l y w i t h the requesting s c i e n t i s t . I t i s important to the progress of the research that he gets what he needs, not n e c e s s a r i l y what he s t a r t e d out asking f o r . There are o p e r a t i o n a l programs which are o f t e n used f o r searches of types 2, 3, 4 and 6 (see Figure 6). No changes may be made i n output headings or formats and, except f o r type 6, no response, dose, or p r o t o c o l c o n d i t i o n s may be imposed. Names of compounds are always added, and we may ask that the computer i n c l u d e s t r u c t u r a l diagrams. I f a d d i t i o n a l s o p h i s t i c a t i o n i s r e q u i r e d , a custom program w i l l be w r i t t e n . The f i r s t four types are probably s e l f - e x p l a n a t o r y . The t h i r d type i n Figure 6 i s most h e a v i l y used. At the end of each monthly merge, a l l 2.5 m i l l i o n records are m i c r o f i l m e d using COM (Computer Output M i c r o f i l m ) a microfilm reader/printer i n a h a l f hour. Suppose the question i s "What do we know about a compound numbered L-475,878?" The answer i s i l l u s t r a t e d i n F i g u r e 7. This t y p i f i e s the answer to the very f i r s t t h i n g we wanted to be able to do - to put a l l the data on a given m a t e r i a l together i n one l i s t i n g . Search type 4 i n Figure 6 i s o r d i n a r i l y requested i n order to review the performance of a p a r t i c u l a r set of compounds i n c e r t a i n t e s t systems. I t a l s o provides a l i s t of those compounds which were not t e s t e d i n the defined s e t . This l i s t can then be sent to Chemdata w i t h a request f o r samples to be submitted f o r the t e s t ( s ) i n q u e s t i o n , i f the asking s c i e n t i s t d e s i r e s . Search type 6 i n Figure 6 i s i l l u s t r a t e d by the h y p o t h e t i c a l c o r r e l a t i o n shown i n Figure 8. A l l compounds which have been examined i n two groups of t e s t s are compared as to s p e c i f i e d responses i n each group. Here 3,600 compounds were t e s t e d both i n v i t r o and i n v i v o . The data show that 87 percent of the compounds a c t i v e i n the t e s t tube were a c t i v e i n mice and that l e s s than 1 percent of the compounds i n a c t i v e i n the t e s t tube were a c t i v e i n mice. Such c o r r e l a t i o n s are u s e f u l i n developing cost e f f e c t i v e t e s t i n g programs, as w e l l as e s t a b l i s h i n g unexpected r e l a t i o n s h i p s . Most r e l a t i o n s h i p s are not so obvious as t h i s , and may r e q u i r e s t a t i s t i c a l a n a l y s i s . S i n g l e record s e l e c t i o n s (Type 5 i n Figure 6) imply that there i s no need to consult any other record to determine whether you wish to save the one at hand. An i n t e r r e c o r d comparison r e q u i r e s , on the other hand, that a set of records i s to be r e t r i e v e d only i f two or more records, e i t h e r i n that set or another, meet some defined c r i t e r i a . " A d d i t i o n a l c o m p l i c a t i o n s " (Type 8 i n Figure 6) covers a m u l t i t u d e of s i n s . The program may be so horrendous that the computer run must be s p l i t up i n t o s e c t i o n s . Many s u b f i l e s may need to be b u i l t . I n t e r f a c e may be necessary with the output of a s t r u c t u r e search from Chemdata.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

I n f e c t i n g organism and s t r a i n and animal species Route of a d m i n i s t r a t i o n of drug and challenge Injection site ED , L D Therapeutic Index, MIC Percent of c o n t r o l Side e f f e c t s - t h r e e - d i g i t code Organ weights, body weight Doses o r concentrations i n v a r i o u s u n i t s , as mg/kg, mcg/ml 50

5 0

Figure 4.

Examples of data captured

Test number f i l e ( a c c e s s i b l e by computer terminal) Index t o Data Sheet f i l e ( a c c e s s i b l e by computer t e r m i n a l ) Search s t a t i s t i c s f i l e (on punched cards) Organism c r o s s - r e f e r e n c e f i l e (on punched cards) Cross reference f i l e s f o r : L-numbers MK-numbers NCI-numbers any other numbers necessary Figure 5.

1· 2. 3. 4. 5. 6. 7. 8.

Other files

No data, e.g., only p r o t o c o l s , counts, e t c . 20 A l l data f o r a p r e v i o u s l y defined s e t of t e s t s 55 A l l data f o r a p r e v i o u s l y d e f i n e d s e t of compounds 134 A l l data f o r a p r e v i o u s l y d e f i n e d s e t of compounds i n a p r e v i o u s l y defined s e t of t e s t s 121 S i n g l e record s e l e c t i o n s , w i t h or without f i l e matching 70 Correlations 7 I n t e r r e c o r d comparisons 185 A d d i t i o n a l complications 22 Total 614 Number r e q u i r i n g s t r u c t u r e s : 148 Figure 6.

Types of searches released—1977

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

93

Except f o r o p e r a t i o n a l programs such as the four noted above, a l l questions i n v o l v e custom programs or manual searches or p o s s i b l y a combination of s e v e r a l methods. Requests to be repeated f a i r l y o f t e n w i l l be catalogued i n our search l i b r a r y . Roughly 65-70 percent of searches i n v o l v e one-time programs. The needs of researchers vary g r e a t l y , depending upon s u b t l e d i f f e r e n c e s which cannot be defined adequately u n t i l they begin to i n t e r a c t w i t h the data bases. Response t o t h i s c o n s t a n t l y changing need i s of utmost importance i n a research environment. The custom programming i s handled by members of the Biodata Department. There are four t e c h n i c a l people and f i v e c l e r i c a l people. A l l are p r e s e n t l y w r i t i n g computer search programs upon demand. These programs are assigned according t o t h e i r current degree of e x p e r t i s e . The 614 searches ru down i n t o the method use The t o t a l , 805, i s g r e a t e r than 614, because some r e q u i r e d more than one method. The 111 persons requesting these 614 searches were 46 chemists, 50 b i o l o g i s t s , and 15 from l e g a l , management, marketing and other i n f o r m a t i o n science areas. The term "The Data A n a l y z e r " i n Figure 9 r e f e r s t o a very e f f i c i e n t FORTRAN-based software package marketed by Program Products, Inc., Nanuet, New York. I t i s used f o r n e a r l y a l l the custom programs. Operations are mostly i n batch mode, although there i s a t e l e t y p e t e r m i n a l , which i s s u i t a b l e f o r subsets of the master f i l e and f o r some s m a l l e r , accessory f i l e s . Each of the 80 characters i n the record i s searchable, as i s any combination thereof. F i e l d s may be defined as r e q u i r e d by each search. S u b f i l e s of records o r p o r t i o n s of records may be created. Computations may be performed on a l l numeric f i e l d s , bearing i n mind that a numeric f i e l d i n one t e s t number may be alpha i n another. Comparing, counting, s o r t i n g are performed as necessary. The records i n computer storage may look very d i f f e r e n t from those presented t o the requesting s c i e n t i s t , depending upon the need of that s c i e n t i s t . The f i n a l output i s t a i l o r e d t o the needs of the s c i e n t i s t . The s i x records i n Figure 10 were combined w i t h names and s t r u c t u r e s from the Chemical Data F i l e s , reformatted, other i n f o r m a t i o n added, and a report produced as shown i n F i g u r e 11. This i s an example of what the s c i e n t i f i c s t a f f i s p r e s e n t l y r e c e i v i n g . The query here was: Produce a report of l a s t week's r a t hypertension data using a p p r o p r i a t e headings f o r each compound i n t h i s order ( l e f t t o r i g h t ) any combining compound number, r a t type, onset time, dose, route of a d m i n i s t r a t i o n , number of r a t s , codes f o r blood pressure change, d u r a t i o n of blood pressure change, heart r a t e change, and date. Omit book and page r e f e r e n c e , t e s t number and v e h i c l e code and add an expanded t e s t t i t l e as a heading. Define a l l codes on each page of

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

A c t i v e i n Mice and A c t i v e i n Test Tube 153 Compounds

O F MEDICINAL

CHEMICAL

INFORMATION

| | |

A c t i v e i n Mice and I n a c t i v e i n Test Tube 19 Compounds

I n a c t i v e i n Mice and | A c t i v e i n Test Tube | 27 Compounds |

I n a c t i v e i n Mice and I n a c t i v e i n Test Tube 3401 Compounds

Of the 180 (153 + 27) compounds a c t i v e i n t e s t tube, 153 (or 87%) are a l s o a c t i v e i n mice. Of the 3420 (340 t e s t tube, 340 mice. Figure 8.

Figure 9.

Correlation study (hypothetical)

Method of solution

Hand Look Up Personal Contact EDP Machine Terminal O p e r a t i o n a l Program Microform The Data Analyzer S t r u c t u r e Driven Other Total

103 4 46 3 172 179 290 3 5 805

62734600L012725H Y PERTEN. RAT

72-15(2) 112

20.

MG/KG5332 121672

62734600L012725HYPERTEN. RAT

7 2 - 1 5 U 112

20.

MG/KG

62734600L012725H Y PE RTEN. RAT

73- 39( ) 112

. 08MG/KG0004 011373 . 02MG/KG0004 011373

92 121672

62734600L012725HYPERTEN. RAT

73- 38(2) 112

62734600L012725H Y PE RTEN. RAT

73- 38(

) 112 06.0

. 02MG/KG0214 011373

62734600L012725HYPERTEN. RAT

73-36(

) 112 01.0

. 08MG/KG0314 011373

Figure 10.

Records in computer storage

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

95

the r e p o r t . Add names and s t r u c t u r e s . D i s t r i b u t e 19 copies to the l i s t of persons designated by Dr. Sweet, who w i l l w r i t e a one page summary cover memo. (This p a r t i c u l a r report was 90 pages long.) Another type of question i n v o l v e s no data d i s p l a y a t a l l , but can i n v o l v e j u s t as much programming. An example i s shown i n F i g u r e 12. The requestor now can r e a d i l y see t h a t , of the 223 compounds t e s t e d , 9 produced a response code of 3, and 1 produced a response code of 1. Note that t h i s may be only 9 compounds, s i n c e o b v i o u s l y there was more than 1 t e s t per compound. Another example might i n v o l v e a new t e s t i n c h i c k s and there are no g u i d e l i n e s except, perhaps, a t i g h t budget. What compounds are there f o r which a p h y s i c a l sample e x i s t s (at l e a s t 250 mg), which were not t o x i c t o c h i c k s at 0.1% i n the d i e t ? The answer t o t h i s questio c h i c k s t r y i n g t o f i n d non-toxi Chemical Data The Chemdata Systems at Merck Sharp & Dohme Research L a b o r a t o r i e s have grown over the past dozen years from a few manual f i l e s to a complete network of i n t e r f a c e a b l e , searchable data bases. For the purpose of comparison, the o r i g i n a l systems c o n s i s t e d of: (1) a chemical s t r u c t u r e f i l e which u t i l i z e d the c l a s s i f i c a t i o n system which was developed by Dr. F. W i s e l o g l e (1) i n 1946; (2) a manual index card f i l e of the sample r e p o s i t o r y ; (3) t r a n s a c t i o n summary sheets c o n t a i n i n g manually posted t r a n s m i t t a l s and; (4) a chemical name f i l e which was a p o r t i o n of the record of the t r a n s a c t i o n summary sheets. Our current computerized i n d i v i d u a l systems, i n c l u d i n g the o r i g i n a l design, content, search and i n t e r f a c e c a p a b i l i t i e s w i t h other systems, are d e s c r i b e d , f o l l o w e d by the enhancements that were added as we gained experience from user i n t e r a c t i o n . An overview summarizes e x a c t l y how the research s c i e n t i s t at MSDRL u t i l i z e s the systems and how he has r e a l i z e d b e n e f i t s therefrom. Chemical Structure Information Systems (CSIS). The most important system i s our Chemical S t r u c t u r e Information System. The d e t a i l s of t h i s system have been published ( 2 ) . However, some major h i g h l i g h t s deserve review. In t h i s system both the updating and the querying of the chemical s t r u c t u r e f i l e begin w i t h t y p i n g the s t r u c t u r e s on a Magnetic T a p e / S e l e c t r i c Typewriter equipped w i t h a t y p i n g e l e ment bearing appropriate bonding c h a r a c t e r s . The tapes a r e processed by computer i n batch mode. For f i l e updates the s t r u c t u r e s are subjected t o numerous v a l i d i t y checks and are analyzed t o create a connection t a b l e and a s s i g n b i t screen elements. Before entry i n t o the master f i l e , newness t o the f i l e i s e s t a b l i s h e d . The e n t i r e i n p u t

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

96

Antihypertensive

Evaluation Codes*

O F MEDICINAL

1 · 20-29 mm Deer

Report No. 256

2 · 30-39 mm Deer

INFORMATION

Heart Rate

Blood Press.

Blood Press. Eff.

Rat Assay

CHEMICAL

1 · Ouest. Chanqe

Duration 1 - Lt 4 hrs

2 - 60-100 Β / M i n e r

3 · GT 40 mm Deer

2 - 4-7

hrs

3 - CT100 B / M I n c r

8 * G T 2 0 m m Deer

3 -GT7hrs

5 - GT 100 B/M Deer

9 · Toxic 0 · No Effect

L-627,346-00L Mol. Wt.

C17H22F3N3O2

357.37

NS Baldwin,

J.J.

M1536-1105-1V

2-[4-(3-tertbutylamino-2-hydroxypr(^

Onset

0 •P.O.

Rat

Time

Dose

Β Τ

Type

Hrs.

Mg/Kg

01

SH

01

SH

01

SH

01

SH

01

SH

CI

SH

Blood

Blood Press. Duration

1 •I. P. 2 •I.V.

Ν α of

20.

1

2

20.

1

9

.08

1

0

0

.02

1

0

06.0

.02

1

01.0

.08

1

Rats

2

Figure 11.

Press. Code

Heart Rate

Code

Code

3

5

Mo Da 12

16

12

16

0

01

13

0

0

01

13

1

2

0

01

13

1

3

0

01

13

3

Final report

408 = Count of t e s t s f o r the p e r i o d 223 = Count of compounds 1 1 0 0 15 9

= = = = = =

Count Count Count Count Count Count

of t e s t s f o r response code 1 of compounds f o r response code 1 of t e s t s f o r response code 2 of compounds f o r response code 2 of t e s t s f o r response code 3 of compounds f o r response code 3

Figure 12.

Bimonthly report for Test X

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

97

Data

r e c o r d , which i n c l u d e s other d e s c r i p t i v e i n f o r m a t i o n , i s s t o r e d i n the computer. Figure 13 represents a chemical s t r u c t u r e record as i t i s input t o the system. The L-number i n the upper l e f t i s the r e g i s t r a t i o n number. This i s f o l l o w e d by the molecular formula, then any stereo d e s c r i p t o r s , reference t o source, and f i n a l l y the chemical s t r u c t u r e . This i s a t y p i c a l s i n g l e record. The f i l e contains approximately 135,000 such records. The year of r e g i s t r a t i o n i s added t o the record a u t o m a t i c a l l y at the time of i t s input t o the system. Tapes bearing s u b s t r u c t u r e queries are processed s i m i l a r l y through e d i t and automatic b i t screen assignment. Although answers may be s e l e c t e d as the r e s u l t of b i t matching alone, t h e search procedure i s normally allowed t o proceed past t h i s stage to the atom-by-atom comparison. Figure 14 l i s t s th capabilities. Figure 15 l i s t s the search parameters which may be invoked i n order t o provide greater s p e c i f i c i t y f o r search q u e r i e s . The CSIS system, as i l l u s t r a t e d i n Figure 16 e x t r a c t s a n c i l l a r y data from the chemical name f i l e , the sample r e p o s i t o r y f i l e and the b i o d a t a f i l e . I n the case of b i o d a t a , i t may be s p e c i f i e d that "ALL" b i o d a t a be p r i n t e d f o r the s p e c i f i c compounds r e t r i e v e d . A d d i t i o n a l c r i t e r i a such as dose and/or a c t i v i t y l e v e l requirements may be i n c l u d e d . The system i s capable of i n t e r r o g a t i n g a customized d i c t i o n a r y of b i o l o g i c a l t e s t t i t l e s s i n g u l a r l y or i n combination, which when n u m e r i c a l l y designated, p r i n t s only those t e s t r e s u l t s stored w i t h i n that d e f i n i t i o n . This data base i s searched n i g h t l y i n batch mode and i s updated on a weekly b a s i s . The s t r u c t u r e f i l e i s capable of being l i n k e d w i t h other MSDRL f i l e s by p r o v i d i n g s t r u c t u r a l i d e n t i f i c a t i o n f o r r e p o r t s upon request throughout MSDRL. Chemical Names. Figure 17 i l l u s t r a t e s the format of the Chemical Name F i l e . Each record contains the r e g i s t r y L-number f o l l o w e d by the chemical name which i n most cases observes CA g u i d e l i n e s . The length of the name i s l i m i t e d t o 180 c h a r a c t e r s . This f i l e i s searchable by L-number and i n some cases by t e x t r e c o g n i t i o n of p o r t i o n s of the name u t i l i z i n g programs w r i t t e n by the departmental s t a f f . Compound Repository. Figure 18 represents the record format of a compound r e p o s i t o r y r e c o r d . The r e g i s t r y number i s f o l l o w e d by the l o c a t i o n d e s c r i p t o r s of each s p e c i f i c sample. The f i l e i s searchable by L-number and contains 125,000 records sequenced i n L-number order. Transaction F i l e .

The most r e c e n t l y developed

system i s

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

O F MEDICINAL

CHEMICAL

INFORMATION

L-590,226-00A C H C1N0 NS WITZEL, Β. M5247-118-5 19

Figure 13.

16

4

CSIS input record

Cl

Total Structure Fragment S t r u c t u r e Multifragment S t r u c t u r e L-number ( S p e c i f i c or Range) Year Plus Fragment S t r u c t u r e Reference Plus Fragment S t r u c t u r e Exact Molecular Formula Plus Fragment S t r u c t u r e Molecular Formulae (Minimum or Exact) Figure 14.

CSIS retrieval capabilities

Statements of i n d e f i n i t e s u b s t i t u e n t s (X's) a t i n d e f i n i t e p o s i t i o n s (Z's) Ring (R) and A c y c l i c (A) d e c l a r a t i o n s I n d e f i n i t e bonds - dotted Apostrophe - r e s t r i c t s s u b s t i t u t i o n Carbon dot - p r o h i b i t s s u b s t i t u t i o n Valence d e c l a r a t i o n s Charge d e c l a r a t i o n s Boolean Logic (AND, OR ( i n c l u s i v e ) , BUT NOT) Repeating u n i t s Abbreviations (Any, None, H a l , Peptides) L i m i t e d r e t r i e v a l volume 500, substructure search Figure 15.

CSIS search variables

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS

Proprietary

ET AL.

Biological

and

Chemical

Data

L-590,226-OOA C H C 1 N 0 Mol. Wt. 357.796 NS WITZEL, Β. M5247-118-5 1 9

1 6

4

CH COOH 2

INDOMETHACIN

L-NUMBER

SALT

590,226 590,226

00 00

2135 2135

A A BATCH 39 47

DESCRIPTION ANALGESIC IN RATS 2175 ANALGESIC IN RATS 2176

LOCATION

CONTAINER

TRAY-0242 TRAY-0249

BOTTLE-036 BOTTLE-017

Figure 16.

L-590,226 OOA

TEST NUMBER

BATCH

CSIS computer report

INDOMETHACIN

L-590,226 04J N,N*-DIBENZYLETHYLENEDIAMINE SALT OF l - ( 4 CHLOROBENZOYD-2-METHYL-5-METHYL-5-METHOXYINDOLE-3-ACETIC ACID L-590,226 07R POTASSIUM l-(4-CHLOROBENZOYL)-5-METHOXY-2METHYL-3-INDOLEACETATE L-590,226 09V MONOBASIC ALUMINUM l-(4-CHLOROBENZOYL)-5METHOXY-2-METHYL-3-INDOLEACETATE L-590,226 16T MIX INDOMETHACIN WITH LACTOSE Figure 17.

Chemical name file

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

99

100

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

the Transaction F i l e Data Base. Figure 19 shows the format of a t y p i c a l record. This system has replaced v i r t u a l l y a l l of the manual record maintenance i n the Chemical Data Department. I t i s r a p i d l y becoming one of the most important systems. The record contains the L-number, date, p r o j e c t and t e s t , sample s i z e , source and requested t e s t i n g a c t i o n to be performed. A l l of these f a c e t s are searchable. This system i s r o u t i n e l y i n t e r f a c e d w i t h the Chemical S t r u c t u r e Information System i n order to provide compound p r o f i l e data f o r users. This f i l e not only gives an h i s t o r i c a l record f o r each compound, but a l s o provides computer generated d e l i v e r y forms w i t h complete i d e n t i f i c a t i o n , which accompany the samples to the t e s t i n g s i t e . This f i l e i s updated d a i l y . Chemdata Enhancements s t r u c t u r e search i s requested most notably b i o l o g i c a l . The o r i g i n a l CSIS design r e q u i r e d the p r i n t i n g of every s t r u c t u r e r e t r i e v e d from a search r e g a r d l e s s of other search c r i t e r i a . In order to accommodate a l l search c r i t e r i a and yet optimize the u t i l i t y of search r e p o r t s , s e v e r a l programs were developed which b a s i c a l l y provide a p r i n t o p t i o n . This o p t i o n i s invoked at the completion of CSIS searches. In e f f e c t , the o p t i o n i s used to r e s t r i c t the chemical answers p r i n t e d from a CSIS search to those w i t h or without b i o l o g i c a l data and/or w i t h or without sample r e p o s i t o r y data. Figure 20 i l l u s t r a t e s the commands which have been incorporated as part of the CSIS search question. Transaction F i l e / I n v e n t o r y . The next major enhancement, c u r r e n t l y under development, i s the Chemical Sample Inventory System which i s part of the o p e r a t i o n a l Transaction F i l e Data Base. This system provides the researcher w i t h an exact amount of compound a v a i l a b l e from the Sample Repository. Knowledge of t h i s i s e s s e n t i a l to those r e s p o n s i b l e f o r overseeing and s e l e c t i n g of compounds f o r both chemical and b i o l o g i c a l t e s t i n g . Without t h i s c a p a b i l i t y , the s e l e c t i o n process becomes d i f f i c u l t ; s u f f i c i e n t s u p p l i e s may or may not e x i s t . I f adequate s u p p l i e s of a chosen candidate do not e x i s t , the process must be repeated and the net e f f e c t i s a c o s t l y waste of research time and t e c h n i c a l manpower. F i l e b u i l d i n g was s t a r t e d by net weighing every new compound submitted to the Sample Repository f o r c a t a l o g u i n g and storage. Concurrently, samples already i n storage were weighed and the net weight data added to the Transaction F i l e . Figure 21 shows how the record looks w i t h t h i s a d d i t i o n a l data. The inventory data are recorded as of a s p e c i f i c date. One of our s t a f f members has w r i t t e n a program which now provides current net weight v a l u e s . This i s accomplished by s u b t r a c t i n g

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

101

COMPOUND LIST AND LOCATION 01/05/78 W. GALL FOR ANTIINFLAMMATORY STUDIES

SEARCH NO. 010377 L-NUMBER

LOCATION

CONTAINER

TRAY-0752 TRAY-0752 TRAY-0752 TRAY-0752 TRAY-0752 SHLF-0011 SHLF-0011

BOTTLE-049 BOTTLE-014 BOTTLE-010 BOTTLE-048 BOTTLE-008 BOTTLE-022 BOTTLE-015

590,226-OOA

Figure 18.

INDOMETHACIN L-590,226-OOA C

1 9

H

1 6

C1N0

4

M o l . Wt.

357.796

NS WITZEL,

Β.

M5247-118-5

CI

BATCH

PROJECT

NO.

NO.

00

00

0001

0001

TEST

DATE

NO.

MO D A Y R

0000

01 18 72

0000

0 1 18 72

SAMPLE SIZE 0000.1000

0005.0000

UNITS GRAM

GRAM

SOURCE DC

DC

COMMENTS F A I N BROWN

ISLAND

BATCH

104

SANDBERG, BATCH

00

0001

0000

0 1 18 72

0010.0000

GRAM

DC

SWEDEN

104

ARMSTRONG, BATCH

Figure 19.

UNIVERSITY,

RHODE

104

Transaction file record

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

CANADA

RETRIEVAL

102

O F MEDICINAL

CHEMICAL

INFORMATION

Β - P r i n t only compounds which do have a l l the requested types of b i o d a t a . NB - P r i n t only compounds which have none of the requested types of b i o d a t a . S - P r i n t only compounds which have sample collection location. NS - P r i n t only compounds which do not have sample l o c a t i o n s . I f both b i o d a t a and sample codes are present, a connective "AND" i s assumed. Figure

INDOMETHACIN L-590.226-OOA C

1 9

H

1 6

C1N0

4

M o l . Wt.

357.796

NS WITZEL,

BATCH NO. 01

PROJECT

TEST

DATE

NO.

NO.

MO D A Y R

0005

1 0 20 77

0000

Β.

M5247-118-5

SAMPLE SIZE 0005.1650

UNITS GRAM

SOURCE SC

COMMENTS INVENTORY/DATE ADDITION

01

1064

0000

1 0 26 77

0000.0050

GRAM

SC

DOUGHERTY FOR FE-SOD

09

2320

9325

1 0 26 77

0000.0200

GRAM

SC

ASSAY

DULANEY FOR IN VITRO

Figure 21.

1482-28

BY PATCHETT

CHEMOTHERAPY

Transaction file/inventory report

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

7.

EGGERS E T A L .

Proprietary

Biological

and

Chemical

Data

103

the weights of samples that have been dispensed from a s p e c i f i c sample a f t e r the inventory weight was recorded. This weight i s then a u t o m a t i c a l l y l i s t e d as the "Net Inventory". See F i g u r e 22. In summary, the "Net Inventory" System coupled w i t h CSIS search r e t r i e v a l , the t r a n s a c t i o n p r o f i l e and b i o d a t a r e s u l t s provides the researcher w i t h the d e s i r e d overview and helps t o p l a n f u t u r e research a c t i v i t i e s . In reviewing the Chemdata Searches completed during 1977 s t a t i s t i c s were compiled as shown i n F i g u r e 23. I t i s obvious f o r one t o conclude that the b i g use of these systems i n v o l v e s the c a t e g o r i e s : (1) s u b s t r u c t u r e search w i t h sample a v a i l a b i l i t y data, and (2) s u b s t r u c t u r e search w i t h b i o l o g i c a l and sample a v a i l a b i l i t y data. Interaction The researcher i s using the systems to uncover new pathways of research by a n a l y z i n g and c o r r e l a t i n g data that are s u p p l i e d from the aforementioned f i l e s . Given an " i d e a " about a s t r u c t u r e / a c t i v i t y r e l a t i o n s h i p , questions a r i s e : 1. Has compound A been i n Test B? 2. I f so, what were the r e s u l t s ? 3. I f not, do we have a sample i n the c o l l e c t i o n ? And 4. i f so, i s there enough m a t e r i a l t o conduct the t e s t ? These systems are becoming more and more important as they grow and i n c l u d e newer research e f f o r t s . Figure 24 i l l u s t r a t e s the i n t e r a c t i o n among the v a r i o u s f i l e s of both b i o l o g i c a l and chemical data which i s now f a i r l y r o u t i n e at MSDRL. The f i r s t two c o n d i t i o n s r e q u i r e examination of the b i o l o g i c a l data. A p o s i t i v e match w i t h the sample a v a i l a b i l i t y f i l e plus a negative match w i t h the s t r u c t u r e c o n s t r a i n t s produce a l i s t of candidate compounds. This l i s t then can be fed back i n t o the Biodata F i l e , the Chemname F i l e , and the S t r u c t u r e F i l e to produce the d e s i r e d r e p o r t . Suppose the answer encompasses 150 compounds and 6 of them look promising on t h i s b a s i s . A s y n t h e t i c program to make analogs may be launched. A new product may r e s u l t .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

O F MEDICINAL

CHEMICAL

INFORMATION

INDOMETHACIN L-590,226 00A C H C1N0 Mol. Wt. 357.796 NS 1 9

1 6

4

W i t z e l , Β. M5247-118-5 01

Net Inventory

5.1400 Gram

Figure 22.

Tray-1208

Bottle-004

Net inventory

CSIS Search T o t a l 1. 2.

T o t a l number of searches conducted T o t a l number of i n d i v i d u a l users A. 74 chemists B. 3 patent attorneys C. 5 biologists D.

695 86

4 other i n f o r m a t i o n departments

Types of Searches 1.

Substructure A. s u b s t r u c t uTypes r e + sample a v a i l a b i l i t y data B. s u b s t r u c t u r e + b i o d a t a C. s u b s t r u c t u r e + b i o d a t a + sample availability D. s u b s t r u c t u r e - compound i d e n t i f i c a t i o n only Registration Identification A. L-number r e g i s t r a t i o n + sample availability B. L-number r e g i s t r a t i o n s + b i o d a t a C. L-number r e g i s t r a t i o n s + b i o d a t a + sample a v a i l a b i l i t y D. L-number r e g i s t r a t i o n s ( i d e n t i f i c a t i o n only) P h y s i c a l Inventory Searches (Operational Nov. 1977) A. L-number + b i o d a t a + p h y s i c a l inventory B. L-number + p h y s i c a l inventory (2 searches Figure 23.

MSDRL—use

i n v o l v i n g 150 compounds) of the Chemdata systems during 1977

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

216 28 313 14

19 28 49 28

100

EGGERS

E T AL.

Proprietary

Biological

and Chemical

Data

Are there any compounds which have: An e l e c t r o s h o c k p r o t e c t i o n ED^Q of <_ 50.0 mg/kg plus an LD^Q j> 2 0 0 . 0 mg/kg, both i n mice, and f o r which we have an a v a i l a b l e sample of a t l e a s t 1 5 0 mg. Given the above c o n d i t i o n s , please d i s p l a y a l l i n v i v o data i n computer storage, together w i t h chemical names and s t r u c t u r e s , but e x c l u d i n g compounds having 7-membered r i n g s , w i t h 5 carbons and 2 n i t r o g e n s 1,4 t o each other. Figure 24.

Biodata/Chemdata interaction to solve query

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

106

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

Acknowledgments Our thanks go to Mr. T. Boyer, A s s i s t a n t D i r e c t o r of Merck Sharp & Dohme Research L a b o r a t o r i e s Information Systems & Programming, Mr. R. T. F o r d , Manager, Research Data P r o c e s s i n g , Mr. W. L . H e n c k l e r , Senior Chemical Information S p e c i a l i s t of the Chemical Data Department, Mr. W. C. Kinahan, S u p e r v i s o r , S c i e n t i f i c Information A n a l y s t of the B i o l o g i c a l Data Department, Mr. F . W. Landgraf, now of Mobay Chemical C o . , Mr. C. J . M i l l e r , Systems P r o j e c t Supervisor and Mr. W. P a t e r , D i r e c t o r of Computer Operations. We a l s o wish to thank many s t a f f members of Merck & C o . , I n c . f o r t h e i r part i n system development. P a r t i c u l a r thanks go to Nancy N i k i p e r and Ann D e N i t t i s f o r a l l the t y p i n g i n v o l v e d . Abstract An open-ended computer system i s described f o r the c o l l e c t i o n , s t o r a g e , r e t r i e v a l and dissemination of b i o l o g i c a l d a t a . Facets of the system i n c l u d e v a r i a b l e u n i t record formats w i t h defined f i e l d s derived from s i g n i f i c a n t aspects of t e s t protocols. I n t e r f a c e i s commonly made w i t h other data bases mentioned below, s i n g l y or i n combination, i n c l u d i n g chemical structure constraints. The common l i n k to the other data bases i s the compound r e g i s t r a t i o n number. Output d i s p l a y may i n c l u d e records from any or a l l of the data bases accessed. Counts, r e s u l t s of computation, or t a b l e s may be i n c l u d e d , as requested by members of the s c i e n t i f i c s t a f f . The Chemical S t r u c t u r e Information System has been p a r t i a l l y described i n 1976 ( 2 ) . The complete network of the chemical and b i o l o g i c a l information systems, i n c l u d i n g Sample Repository Data Base, Transaction F i l e Data Base, as w e l l as Chemical Name Data Base, i s d e s c r i b e d . Searches performed during a recent calendar year on Biodata and Chemdata Systems have been analyzed, and the r e s u l t s are discussed w i t h emphasis on the i n t e r p l a y between the chemical s t r u c t u r e , s u b s t r u c t u r e and b i o l o g i c a l data segments of the o v e r a l l system. Literature

References

1.

Emmett L . Buhle, E l i n o r D. Hartnell, Alexander M. Moore, Louise R. W i s e l o g l e , and F . Y . W i s e l o g l e "A New System f o r the Classification of Compounds: A C o n t r i b u t i o n from the Survey of A n t i m a l a r i a l Drugs", J. Chem. Ed., 23., 375 (1946).

2.

Horace D. Brown, Marianne Costlow, Frank A . C u t l e r , Jr., A l b e r t N . Demott, Walter B . Gall, David P. Jacobus, and Charles J. Miller "The Computer-Based Chemical Structure Information System of Merck Sharp & Dohme Research L a b o r a t o r i e s " , J . Chem. I n f . and Computer Sci., 16, 5 (1976).

RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Progress toward an On-Line Chemical and Biological I n f o r m a t i o n S y s t e m at t h e

Upjohn

Company

W. J. HOWE and T. R. HAGADONE The Upjohn Company, Kalamazoo, MI 49001

Over the past t e n a c e u t i c a l i n d u s t r y have way computers are utilized in research and research support functions. E a r l y a p p l i c a t i o n s tended to focus on numerical tasks such as statistical analyses and quantum mechanical c a l c u l a t i o n s o r on the a r c h i v a l storage of i n f o r m a t i o n r e l a t e d to the chemistry o r b i o l o g y of research substances. I n the latter case, i n f o r m a t i o n retrieval systems were often u n w i e l d l y and r e q u i r e d c o n s i d e r a b l e e x p e r t i s e f o r their use. The l a b o r a t o r y researcher u s u a l l y had to work through an intermediary in order to r e t r i e v e i n f o r m a t i o n from such systems. More r e c e n t l y , we have seen a shift of emphasis to where computers are now recognized as i n d i s p e n s a b l e t o o l s in the day-to-day o p e r a t i o n of scientific research. On-line i n t e r a c t i v e methods have placed the i n f o r m a t i o n resource much c l o s e r to the end u s e r . I n a d d i t i o n to their "traditional" a p p l i c a t i o n s , computer-based systems are being employed to assist in the design of organic syntheses, in the interpretation of s p e c t r o s c o p i c d a t a , i n the design and development of new drug candidates, f o r r e a l - t i m e experiment c o n t r o l , and in a wide variety of r e l a t e d areas (1-6)· The retrieval and m a n i p u l a t i o n of m e d i c i n a l chemical i n f o r m a t i o n is another area in which computer—based systems have made an i m pact and which will become i n c r e a s i n g l y important in future y e a r s . This paper w i l l focus on a p r o j e c t which has been under way at the Upjohn Company to develop a comprehensive chemical and b i o l o g i c a l i n f o r m a t i o n system to be used by research s c i e n t i s t s and research support p e r s o n n e l . C a p a b i l i t i e s of the system w i l l event u a l l y i n c l u d e o n - l i n e s t r u c t u r e r e g i s t r y , s t r u c t u r e and s u b s t r u c ture s e a r c h i n g , the r e t r i e v a l and m a n i p u l a t i o n of pharmacological t e s t data, and the r e t r i e v a l of s p e c t r o s c o p i c , p a t e n t , and other types of s t r u c t u r e - a s s o c i a t e d d a t a . There are c u r r e n t l y a number of systems i n the company which are being used f o r the storage of b i o l o g i c a l data a s s o c i a t e d w i t h compounds that have been s y n t h e s i z e d f o r s c r e e n i n g . I n most cases, the o p e r a t i o n of these systems has i n the past been q u i t e i n d e pendent of " c h e m i c a l l y - o r i e n t e d " i n f o r m a t i o n . Chemical s t r u c t u r e 0-8412-0465-9/78/47-084-107$06.25 Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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and s u b s t r u c t u r e searching has been accomplished through the use of a fragment code which was developed i n the l a t e 1950's, and which, d e s p i t e a number of drawbacks that are commonly inherent i n fragment-based systems, has met the needs of our s c i e n t i s t s f o r a number of y e a r s . However, s i n c e one of the goals of the new i n formation system i s to p r o v i d e a means f o r i n t e r a c t i v e l y a c c e s s i n g both the chemical s t r u c t u r e data and a s s o c i a t e d pharmacological data, and f o r the e x t r a c t i o n of subgroups of compounds which could then, f o r example, a c t as source data f o r end-user a p p l i c a t i o n s such as p a t t e r n r e c o g n i t i o n a n a l y s e s , the design of a f l e x i b l e and e f f i c i e n t chemical s t r u c t u r e entry and search system became the i n i t i a l t a r g e t of our a t t e n t i o n . The chemical s t r u c t u r e system c o n s i s t s of three p a r t s , i n d i f f e r e n t stages of development: (a) the s t r u c t u r e database, a c o l l e c t i o n of approximately 60,000 chemical s t r u c t u r e t i o n of which has (b) the s t r u c t u r e entry system, an i n t e r a c t i v e computer-graphics based system which was developed t o create the i n i t i a l d a t a base; p o r t i o n s of t h i s w i l l a l s o be i n c o r p o r a t e d i n the compound r e g i s t r y and search system, (c) the compound r e g i s t r y and search system, c u r r e n t l y under development, which c o n s i s t s of two p a r t s : (1) an o n - l i n e r e g i s t r y f a c i l i t y which w i l l a l l o w i n t e r a c t i v e d a i l y updating of the database, and, (2) the query f a c i l i t y , which w i l l a l l o w o n - l i n e i n t e r a c t i v e s t r u c t u r e and s u b s t r u c t u r e searching and e v e n t u a l searching and m a n i p u l a t i o n of a s s o c i a t e d pharmacological i n f o r m a t i o n . The system w i l l enable the user t o d i s p l a y the r e t r i e v e d i n f o r m a t i o n i n a convenient format and to produce h i g h q u a l i t y hard copy output of both s t r u c t u r a l and t e x t u a l data. 1.

The S t r u c t u r e Database

A key phase of the p r o j e c t i n v o l v e d the c r e a t i o n of the s t r u c t u r e database, a g r a d u a l l y e n l a r g i n g c o l l e c t i o n of a p p r o x i mately 60,000 chemical s t r u c t u r e s which over the years had e i t h e r been synthesized in-house f o r t e s t i n g purposes o r obtained from o u t s i d e o r g a n i z a t i o n s . The fragment-coded search system a l s o operated on t h i s c o l l e c t i o n of compounds; however, s i n c e fragment codes represent s t r u c t u r a l a t t r i b u t e s , the codes could not be used to regenerate complete connection t a b l e s . A s t r u c t u r e entry system was designed which, by using computer g r a p h i c s as the input medium, would a l l o w d i r e c t t r a n s c r i p t i o n of the s t r u c t u r e diagrams from hard copy format i n t o the computer system. Connection t a b l e s would be generated i n r e a l - t i m e as the s t r u c t u r e drawing o p e r a t i o n progressed. The s t r u c t u r e e n t r y program was ready f o r use about 1-1/2 years ago and f u l l s c a l e s t r u c t u r e e n t r y began a t the s t a r t of 1977. Although many

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e r r o r - d e t e c t i o n devices were b u i l t i n t o the system, there were s t i l l c e r t a i n types of e r r o r s which could s l i p by and enter the data base. For that reason i t was decided at the outset t h a t each s t r u c t u r e would have to be entered t w i c e , by d i f f e r e n t t e r m i n a l operators, thereby enabling an i d e n t i t y check to be performed on the host computer. E r r o r checking by manual comparison of each entered s t r u c t u r e w i t h a hard copy record would, i t was f e l t , take j u s t as long as i t would take to redraw a s t r u c t u r e a second time and would s t i l l provide no guarantee that a l l e r r o r s had been caught. The s t r u c t u r e entry o p e r a t i o n has j u s t r e c e n t l y been comp l e t e d , having taken c o n s i d e r a b l y l e s s time than o r i g i n a l l y a n t i c i p a t e d . Now that the high volume input of the database "backlog" i s done, i t i s planned that r o u t i n e d a i l y update of the database w i t h low volume " c u r r e n t " s t r u c t u r e s w i l l be handled by the onl i n e r e g i s t r y f a c i l i t y whic be discussed l a t e r . 2.

The S t r u c t u r e Entry System

The s t r u c t u r e entry system was designed to accommodate r a p i d e r r o r - f r e e s t r u c t u r e e n t r y , w i t h much c o n s i d e r a t i o n given t o s t r u c t u r e diagram cosmetics. I t was a l s o designed so that i t could be e a s i l y i n c o r p o r a t e d i n t o the compound r e g i s t r y and search system w i t h l i t t l e or no m o d i f i c a t i o n . For that reason, we w i l l present an o p e r a t i o n a l overview of the g r a p h i c a l s t r u c t u r e e n t r y system, f o c u s i n g i n p a r t i c u l a r on i t s use i n the c r e a t i o n of the s t r u c t u r a l database. (a) Hardware. The data entry t e r m i n a l i s operated essent i a l l y as a stand-alone computer system (Figure 1) which t r a n s mits completed s t r u c t u r e connection t a b l e s to the host machine (370/155) where they are compared a g a i n s t t h e i r d u p l i c a t e s t r u c tures (double e n t r y ) . Once a day an e r r o r l o g i s p r i n t e d to enable c o r r e c t i o n of s t r u c t u r a l e r r o r s (using a s i m i l a r program on the database management t e r m i n a l , see Figure 1). The s t r u c t u r e entry system c o n s i s t s of a PDP 11/04 computer w i t h 28K words of memory, a dual f l o p p y - d i s k d r i v e , keyboard, graphics t a b l e t , and CRT ( s i m i l a r to the DEC GT43 package). The graphics t a b l e t and a s s o c i a t e d s t y l u s enable a user to i n t e r a c t w i t h the d i s p l a y by moving the s t y l u s on the surface of the t a b l e t , r a t h e r than p o i n t i n g to the face of the scope as would be done w i t h a l i g h t pen. Software i n the computer t r a c k s the motion of the s t y l u s w i t h a cursor (a s m a l l cross) on the scope. Depressing the s t y l u s a c t i v a t e s a s w i t c h i n the s t y l u s t i p which i n t u r n allows the user to s e l e c t options from a "menu" on the d i s p l a y . Such a device has been found to be a very n a t u r a l medium f o r i n t e r a c t i n g w i t h a d i s p l a y and much more convenient than a l i g h t pen. A d d i t i o n a l det a i l s on the use of a graphics t a b l e t f o r chemical s t r u c t u r e drawing can be found i n references 7_ and 8_.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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O F MEDICINAL

CURRENT [ STRUCTURE I ι DATABASE,

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INFORMATION

FUTURE f STRUCTURE I DATABASE,

HOST MACHINES

IBM 370/155 OS/VS1

COMMUNICATION CONTROLLER

FLOPPY DISK (DSD-210)

PROGRAM DEVEL OPMENT & STRUC TURE CORRECTION SYS. (PDP11/40)

GRAPHICS, KEYBOARD, TABLET

STRUCTURE ENTRY SYSTEM (PDP11/04)

PRINTER/ PLOTTER (VERSATEC)

FLOPPY DISK

GRAPHICS, KEYBOARD, TABLET

Figure 1. Hardware configuration for structure-entry project. High-volume structure entry was accomplished on the small graphics system (PDP 11/04); data base was formed on 370/155. Data-base maintenance and structure corrections were performed on the large graphics system (PDP 11/40). Information-retrieval-system-runs on 370/ 148 with data base transferred from 370/155.

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At times the host machine i s not a v a i l a b l e , and so r a t h e r than t r a n s m i t t i n g completed s t r u c t u r e s d i r e c t l y to the database on the 370, the program i n s t e a d w r i t e s them on a flopp y d i s k . These are l a t e r incorporated i n t o the database v i a the flopp y d i s k u n i t on the second graphics t e r m i n a l (see Figure 1). (b) I n t e r n a l S t r u c t u r e Representation. S t r u c t u r e s are r e presented i n the computer i n the form of atom-bond connection t a b l e s . These are arrays of data which account f o r such things as: ( i ) f o r each atom; atom type, formal charge, i s o t o p e l e v e l , presence of unpaired e l e c t r o n , two-dimensional c o o r d i nates, number of bonds attached, and a d d i t i o n a l i n f o r mation r e q u i r e d f o r regeneration of the s t r u c t u r e d i a gram, ( i i ) f o r each bond the bond, bon mation f o r cases where the bond i s attached to a c h i r a l atom. The connection t a b l e i s formed i n c r e m e n t a l l y during the s t r u c t u r e drawing o p e r a t i o n . Since X-Y coordinate data f o r each atom are stored i n the t a b l e , a complete molecular p i c t u r e can be generated almost i n s t a n t a n e o u s l y from the connection t a b l e . The t a b l e provides an unambiguous r e p r e s e n t a t i o n of a s t r u c t u r e ; how ever, a t the time the connection t a b l e i s i n s e r t e d i n the data base, a c a n o n i c a l i z a t i o n step (using a modified Morgan a l g o r i t h m (9j10)) i s performed which r e s u l t s i n a unique o r d e r i n g of the atoms w i t h i n the t a b l e and f a c i l i t a t e s a d i r e c t comparison of two " d u p l i c a t e " t a b l e s to detect d i f f e r e n c e s ( e r r o r s ) . The connection t a b l e that i s s t o r e d contains no h i g h e r - l e v e l chemical i n f o r m a t i o n such as a r o m a t i c i t y , r i n g i n f o r m a t i o n , o r stereochemical r e l a t i o n ships other than the bond type t r a n s c r i b e d from the hard copy r e cord. Such h i g h - l e v e l r e l a t i o n s h i p s (and others) can be e x t r a c t e d from the b a s i c i n f o r m a t i o n contained i n the t a b l e by a p p r o p r i a t e p e r c e p t i o n r o u t i n e s on the host machine. In f a c t , the s t r u c t u r e record that w i l l be used f o r high speed s u b s t r u c t u r e searching i s not the o r i g i n a l master connection t a b l e (CT) f o r each s t r u c t u r e , but a s p e c i a l l y formatted record derived from the CT which a l s o contains a l l the h i g h e r - l e v e l data necessary to provide search r e s u l t s i n as c l o s e to " i n t e r a c t i v e time" as p o s s i b l e (see d i s c u s s i o n of s u b s t r u c t u r e s e a r c h i n g ) . Thus, the c o n n e c t i v i t y informa t i o n w i l l a c t u a l l y be present i n more than one form i n the com p l e t e d r e g i s t r y and search system. In the f o l l o w i n g d i s c u s s i o n , however, "connection t a b l e " r e f e r s to the expanded c o n n e c t i v i t y array described at the s t a r t of t h i s s e c t i o n . (c) G r a p h i c a l S t r u c t u r e Input. S t r u c t u r e s are t r a n s c r i b e d i n t o the system from data sheets which c o n t a i n molecular formula, chemical name, s t r u c t u r e diagram, some p h y s i c a l and b i o l o g i c a l screening data, and a r e g i s t r y number c a l l e d a "U-number". I n

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some r e s p e c t s , the g r a p h i c a l entry system i s s i m i l a r to those used by Chemical A b s t r a c t s S e r v i c e (11) f o r s t r u c t u r e input and by com p u t e r - a s s i s t e d s y n t h e s i s research groups (12 1Ζ 1) f o r s p e c i f i c a t i o n of t a r g e t molecules. There a r e , however, a number of d i f f e r ences from the l a t t e r systems due to our r e q u i r e d focus on e r r o r c o n t r o l , speed of e n t r y , and o v e r a l l s t r u c t u r e diagram cosmetics. A number of drawing options appear on the d i s p l a y , which es s e n t i a l l y represent a "menu" of graphics c o n t r o l s . To s e l e c t from the menu the user moves the s t y l u s on the t a b l e t so as to super impose the t r a c k i n g cursor on one of the o p t i o n s , and then de presses the s t y l u s s l i g h t l y to a c t i v a t e the d e s i r e d o p t i o n . As can be seen i n F i g u r e 2, at the top of the d i s p l a y a r e c t a n g l e appears around the TYPE o p t i o n . This i n d i c a t e s to the operator the o p t i o n that i s c u r r e n t l y a c t i v e . Some i n f o r m a t i o n must be entered v i a the keyboard This i n cludes the date and th s e s s i o n ) , and a U-numbe s t r u c t u r e i s drawn. The system matches the MF a g a i n s t the s t r u c ture when the OUTPUT o p t i o n i s s e l e c t e d and only t r a n s m i t s the s t r u c t u r e to the database i f the MF and s t r u c t u r e match. The l a r g e r e c t a n g l e i n the center of the d i s p l a y represents the drawing area i n s i d e which the molecular diagram i s c o n s t r u c t ed. E r r o r messages and other t e x t u a l feedback to the user appear at the bottom of the drawing area. The options which are arrayed along the top of the d i s p l a y a l l o w the user to change drawing modes. They operate as f o l l o w s . DRAW allows the user to perform a freehand drawing o p e r a t i o n to enter bonds and i m p l i c i t carbon atoms (see below f o r d e s c r i p t i o n ) ; RINGS changes the d i s p l a y to a second menu from which pre-drawn r i n g systems can be s e l e c t e d ; MOVE enables the user to a d j u s t the p o s i t i o n of atoms and t h e i r attached bonds by simply superimposing the cursor on the d e s i r e d atom and moving the s t y l u s (and thereby, the atom) to i t s new p o s i t i o n ; CENTER centers the drawing i n the box; DELETE a l l o w s the s e l e c t i v e erasure of atoms or bonds; TYPE r e t u r n s c o n t r o l to the keyboard; OUTPUT sends a completed s t r u c t u r e to the host machine a f t e r the molecule i s subjected to a s e r i e s of e r r o r checks (remaining e r r o r s are detected on the 370 during the d u p l i c a t e match); and CLEAN erases the drawing area and i n i t i a l i z e s the connection t a b l e . The three remaining options at the top of the d i s p l a y are f o r bond character m o d i f i c a t i o n . For example, the broken/zigzag l i n e allows s p e c i f i c a t i o n of stereochemical i n f o r m a t i o n . While the system i s i n t h i s mode, the user can " p o i n t to the center of a bond and i t w i l l become a dashed bond to i n d i c a t e a p r o j e c t i o n of the bond back i n t o the plane of the drawing. P o i n t i n g to the bond a second time converts i t to a "wavy" bond of the type normally used to i n d i c a t e undefined absolute c o n f i g u r a t i o n at a c h i r a l center. So f a r , t h i s has been s u f f i c i e n t to permit an adequate s p e c i f i c a t i o n of stereochemistry; however, i n the next v e r s i o n of the g r a p h i c a l e n t r y system wedge-shaped bonds w i l l be s p e c i f i a b l e , 3

9

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to i n c r e a s e the f l e x i b i l i t y of the system and prevent any ambig u i t y of c h i r a l s i t e d e f i n i t i o n . The arrow o p t i o n above DELETE i s used f o r the s p e c i f i c a t i o n of s t r o n g l y p o l a r i z e d bonds where there i s a formal charge separat i o n between the ends of the bond. This can be used i n N-oxides or phosphates, f o r example. The r e g i s t r y and search system w i l l recognize the equivalence of R 3 N — > 0 and R 3 N 0 , so the a r row i s used mainly f o r cosmetic purposes without any l o s s o f s t r u c t u r a l i n f o r m a t i o n . And f i n a l l y , the s o l i d l i n e a t the top of the d i s p l a y i s used t o convert any of the s p e c i a l bond types j u s t described back t o a normal s i n g l e bond. Along the bottom of the d i s p l a y appear a number of commonlyo c c u r r i n g atom types and f u n c t i o n a l groups, as w e l l as some cont r o l o p t i o n s . The FLIP o p t i o n changes the bottom menu t o r e v e a l an a d d i t i o n a l s e t of l e s s commonly-occurring atoms and groups. F u n c t i o n a l groups not presen simply by s e l e c t i n g th n e c t i n g them w i t h the a p p r o p r i a t e bonds. T h i s , however, takes longer than i t does t o i n s e r t one of the predrawn groups. Many of the predrawn f u n c t i o n a l groups can a l s o be converted t o s t r u c t u r a l l y s i m i l a r groups. For example, t o draw a t r i c h l o r o m e t h y l group, the operator would (a) i n s e r t a C F 3 from the menu, (b) p i c k up a CI from the menu and superimpose i t on the F 3 i n the t r i f l u o r o m e t h y l group, and (c) depress the s t y l u s . This would immediately convert the C F 3 t o a C C I 3 . Since the C C I 3 i s r e p r e sented i n the connection t a b l e as three d i s t i n c t c h l o r i n e atoms attached t o the same carbon, the operator could a l s o enter the same group by drawing the three c h l o r i n e s s e p a r a t e l y . Although the appearance would be d i f f e r e n t , the c o n n e c t i v i t y data f o r the two forms would be the same. At the s t a r t o f each s t r u c t u r e drawing o p e r a t i o n , the comput e r requests the U-number and molecular formula of the compound. A f t e r t h i s i n f o r m a t i o n i s typed i n by the o p e r a t o r , the t a b l e t i s a c t i v a t e d and the p i c t u r e drawing stage can begin. Although there i s no drawing order imposed on the o p e r a t o r , the c y c l i c nucleus of the molecule i s u s u a l l y drawn f i r s t . Rings can be drawn i n two ways, freehand o r by s e l e c t i n g a predrawn r i n g system from the second d i s p l a y . To draw a bond "freehand", the user s e l e c t s the DRAW o p t i o n and then depresses the s t y l u s w i t h the cursor i n s i d e the drawing area. As the s t y l u s i s moved, a s t r a i g h t l i n e appears on the scope as i f i t were " i n k " from the s t y l u s . When the s t y l u s i s l i f t e d , the l i n e i s f r o z e n and the new bond i s i n s e r t e d i n the connection t a b l e . The t e r m i n a t i n g atoms are i n i t i a l l y assumed t o be carbon. A d d i t i o n a l bonds can be drawn i n t h i s manner u n t i l the d e s i r e d r i n g i s formed. We have found, however, that the entry o p e r a t i o n can be speeded up c o n s i d e r a b l y by p r o v i d i n g a c o l l e c t i o n of predrawn r i n g systems which can be brought i n t o view (Figure 3) by p r e s s i n g the RINGS o p t i o n . +

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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This f e a t u r e provides an a d d i t i o n a l b e n e f i t i n that most o f the r e s u l t i n g r i n g s are r e g u l a r , have s i m i l a r edge l e n g t h s , and can be l i n k e d together q u i t e e a s i l y . To p i c k up one of the r i n g s , the operator depresses the s t y l u s on the numeric symbol i n s i d e the appropriate r i n g . The d i s p l a y changes back a u t o m a t i c a l l y (to Figure 2) and the s e l e c t e d r i n g p i c t u r e becomes the new s t y l u s c u r s o r , f o l l o w i n g the s t y l u s motion. The user moves the r i n g to the a p p r o p r i a t e p o s i t i o n on the screen and depresses the s t y l u s again. This a c t i o n causes the r i n g atoms and bonds to be i n s e r t e d i n the connection t a b l e and the r i n g to be f r o z e n at t h a t p o s i t i o n on the scope. But s i n c e the o r i g i n a l r i n g i s s t i l l t r a c k i n g the s t y l u s , a d d i t i o n a l r i n g s can be i n s e r t e d , e i t h e r s e p a r a t e l y or l i n k e d together. The program a u t o m a t i c a l l y takes care of shared bonds ( f u s i o n ) o r shared atoms ( s p i r o or b r i d g i n g systems) as r i n g networks are b u i l t up during the r i n g l i n k i n leased from the s t y l u s soon as the r i n g cursor i s moved o u t s i d e the drawing area. We have found that t h i s allows the operator to b u i l d complex r i n g systems q u i t e r a p i d l y and e l i m i n a t e s the many diagram a d j u s t ments (using the MOVE option) that would otherwise have to be made. To i n s e r t non-carbon atomic symbols, the user depresses the s t y l u s on the d e s i r e d atom at the bottom of the d i s p l a y . The t r a c k i n g cursor disappears and i s replaced by a copy of the s e l e c ted atomic symbol. This can then be moved i n t o p o s i t i o n i n the developing molecule by depressing the pen at the appropriate p o s i t i o n , causing a new atom to be created o r a p r e v i o u s l y e x i s t i n g atom to be converted to the new atom type. Attached bonds are a u t o m a t i c a l l y s h i f t e d back s l i g h t l y to make room f o r the new atom symbol. Groups of atoms and f u n c t i o n a l groups can be i n s e r t e d i n a s i m i l a r manner. When a f u n c t i o n a l group i s s e l e c t e d from the menu and p o s i t i o n e d i n the developing molecule, the program does not simply adjust the p i c t u r e to d i s p l a y the new group. Rather, t h e system modifies the connection t a b l e to i n c l u d e the new informat i o n . In the case of a n i t r i l e group, f o r example, carbon, n i t r o gen, and t r i p l e bond e n t r i e s are a u t o m a t i c a l l y i n s e r t e d i n the t a b l e . The p i c t u r e i s then regenerated from the updated CT. I n f a c t , any m o d i f i c a t i o n of the s t r u c t u r e i s accompanied i n r e a l time by a corresponding connection t a b l e update. As each drawing o p e r a t i o n i s performed, the program executes a valence check. Thus, the attachment to an atom of excess bonds or the conversion of a fully-bonded atom to an atom type of lower valence i s prevented and accompanied by an appropriate message t o the operator. I n s e r t i o n of a charge on an atom ( v i a the + o r "-" options at the bottom of the d i s p l a y ) allows attachments i n excess o f the normal valence to be made. A c y c l i c atomic chains can be drawn by p i c k i n g up the cons t i t u e n t groups and atoms from the menu, i n s e r t i n g them i n the lf

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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drawing, and then bonding them together using the DRAW o p t i o n . However, t h i s approach tends t o be slow and connecting bonds can be l e f t out i n a d v e r t e n t l y ( t h i s c o n d i t i o n would be i d e n t i f i e d by the e r r o r check when the OUTPUT o p t i o n i s pressed). The user i n s t e a d g e n e r a l l y s e l e c t s one of the four arrow opt i o n s from the bottom of the d i s p l a y (Figure 2 ) . When the s t y l u s i s then depressed on an atom, a b l i n k i n g arrow appears beside the atom, p o i n t i n g i n the d i r e c t i o n of d e s i r e d chain extension. As long as the b l i n k i n g arrow remains on an atom, groups o r atoms can be a u t o m a t i c a l l y i n s e r t e d and bonded w i t h even spacing simply by depressing the s t y l u s on the d e s i r e d atom or group o p t i o n a t the bottom. By c o n t r a s t , w i t h the arrow o f f , s e l e c t i o n of a group o r atom r e s u l t s i n the cursor being replaced by a copy of the group or atom symbol; the user must then move i t up t o the c o r r e c t p o s i t i o n f o r i n s e r t i o n . By t h i s "automatic i n s e r t i o n " method, a c y c l i c chains can be constructe motion. Sequence I-VII d e p i c t s the v a r i o u s stages o f chain growth f o r a sample molecule. As each atom o r group i s added, the b l i n k i n g arrow moves over (assuming no valence i n f r a c t i o n r e s u l t e d from the i n s e r t i o n ) t o remain a t the end of the developing chain. I f the group w i t h which the arrow i s a s s o c i a t e d i s a ( C H 2 ) 2 u n i t , dep r e s s i n g the (CH2) o p t i o n causes the s u b s c r i p t t o be incremented (up t o a maximum of ( ^ 2 ) 3 0 ) » w h i l e the arrow stays i n p l a c e . The connection t a b l e i s updated t o r e f l e c t the f a c t t h a t there are now three connected methylene u n i t s ( i n s t r u c t u r e VI) w i t h the same coordinates. When a group i s added which has no remaining f r e e valence (such as a n i t r o or methoxy), the arrow turns o f f . A t any time the arrow can be turned o f f o r pointed i n another d i r e c t i o n by s e l e c t i n g any of the other options on the d i s p l a y , i n c l u d i n g a d i f f e r e n t arrow o p t i o n . F i g u r e 5 i l l u s t r a t e s a molecule being developed w i t h the a s s i s t a n c e of the b l i n k i n g arrow o p t i o n . The program a l s o provides the c a p a b i l i t y f o r handling compounds w i t h more e x o t i c s t r u c t u r a l r e l a t i o n s h i p s , such as those e x e m p l i f i e d i n VIII-X. Compound VIII represents a mixture of two m o e i t i e s i n a 200:1 molar r a t i o . S t r u c t u r e IX has a n o n - i n t e g r a l number of moles o f methanol and an undetermined number of moles of water s o l v a t e d t o the main s t r u c t u r a l u n i t . Compound X represents a pure compound w i t h u n i d e n t i f i e d stereochemistry a t the asymmetric double bond. S t r u c t u r e s which c o n t a i n incompletely defined p o s i t i o n i n g of r i n g s u b s t i t u e n t s , f o r example, could a l s o be handled i n a manner s i m i l a r t o I . I n a newer v e r s i o n of the g r a p h i c a l entry system being designed f o r use i n the r e g i s t r y and search system, p r o v i s i o n i s being made f o r p o l y p e p t i d e s , p o l y n u c l e o t i d e s , metallocenes, and metal c o o r d i n a t i o n complexes which cannot c u r r e n t l y be handled. When the entry o f a s t r u c t u r e has been completed the operator depresses the s t y l u s on the OUTPUT o p t i o n . The software checks f o r missing bonds ( u n f i l l e d valences on atoms f o r which attached hydrogens are not i m p l i e d ) , unbalanced atomic charges, and m i s -

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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HOWE AND HAGADONE

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Automatic chain extension with arrow option (arrow is on CH)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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matches between the MF and the s t r u c t u r e (Figure 6). I f an e r r o r i s detected, a message i s d i s p l a y e d at the bottom of the screen e x p l a i n i n g the problem. I f p o s s i b l e , the program w i l l i d e n t i f y the molecular s i t e at which the e r r o r e x i s t s . I n the example i l l u s t r a t e d i n F i g u r e 6 the molecular formula was i n c o r r e c t and would have to be retyped. A number of e r r o r s that have e x i s t e d even on the o r i g i n a l data sheets have been i d e n t i f i e d by t h i s approach and c o r r e c t e d . The f i n i s h e d s t r u c t u r e i s t r a n s m i t t e d to the database on the 370 where any remaining e r r o r s such as misplaced s u b s t i t u e n t s or i n a c c u r a t e l y s p e c i f i e d stereochemistry are flagged by the d u p l i c a t e checking o p e r a t i o n f o r l a t e r c o r r e c t i o n . Only i n the u n l i k e l y event that two operators make i d e n t i c a l e r r o r s of the two kinds j u s t mentioned w i l l i n c o r r e c t s t r u c t u r e s a c t u a l l y enter the permanent database. As i s evident from the above d i s c u s s i o n , c o n s i d e r a b l e importance has been attache diagrams as they are i n s e r t e reasons f o r t h i s are: (a) the planned i n c l u s i o n i n the r e g i s t r y and search system of a r e p o r t generation f a c i l i t y (high q u a l i t y s t r u c t u r e p l o t s are a l r e a d y being generated from the database f o r i n s e r t i o n i n the data sheets of " c u r r e n t " compounds), and (b) the d e s i r e f o r neat, unambiguous, and c o n s i s t e n t ( w i t h i n groups of s t r u c t u r a l analogs) d i s p l a y s of compounds r e t r i e v e d by users of the r e g i s t r y and search system. I t should be s t r e s s e d , however, that when a user draws a s t r u c t u r e or s u b s t r u c t u r e i n t o the s y s tem as the t a r g e t of a search, there need be no concern whatever f o r s t r u c t u r e diagram cosmetics. S t r u c t u r e s can be drawn u s i n g the freehand techniques d e s c r i b e d e a r l i e r , w i t h convoluted and uneven r i n g s , f o r example, without a f f e c t i n g the accuracy of the search. Thus, a novice user w i l l s t i l l be able to perform searches without having to l e a r n the f i n e p o i n t s of r i n g network c o n s t r u c t i o n , automatic c h a i n lengthening, f u n c t i o n a l group i n t e r c o n v e r s i o n , and so on. 3.

The Compound R e g i s t r y and Search System

The compound r e g i s t r y and search system provides the graphi c a l user^ i n t e r f a c e , i n t e r a c t i v e command language, search funct i o n s , and database management support which a l l o w compound-assoc i a t e d i n f o r m a t i o n to be added to the database and e x i s t i n g data to be m o d i f i e d or queried. The r e g i s t r y f a c i l i t y i s a v a i l a b l e on a r e s t r i c t e d b a s i s to those users w i t h a u t h o r i t y to update the compound database. On the other hand, the query f a c i l i t y i s a v a i l a b l e to a l l users and a l l o w s search, d i s p l a y , and hard copy output of the v a r i o u s types of i n f o r m a t i o n s t o r e d i n the databasa (a) The R e g i s t r y F a c i l i t y . The p r i n c i p a l f u n c t i o n of r e g i s t r y i s to a l l o w chemical s t r u c t u r e i n f o r m a t i o n on compounds newly submitted f o r b i o l o g i c a l screening to be entered i n t o the compound database. Although f u l l o p e r a t i o n of the r e g i s t r y por-

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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t i o n of the system i s s t i l l s e v e r a l months away, the design has been completed and implementation i s now i n progress. The major components of the f a c i l i t y i n c l u d e : (a) a g r a p h i c a l s t r u c t u r e entry and d i s p l a y subsystem embodying a l l the features of the s t r u c t u r e e n t r y package j u s t discussed, (b) a command language, i n t e r p r e t e d by the host p r o c e s s o r , and (c) a v a r i e t y of search, update, and d e l e t i o n f u n c t i o n s . Commands entered at the keyboard of the g r a p h i c s t e r m i n a l appear on the scope and are s i m u l t a n e o u s l y t r a n s m i t t e d to the 370 f o r i n t e r p r e t a t i o n . I f an a u t h o r i z e d user wishes to r e g i s t e r a new compound, the host machine s i g n a l s the graphics system to act i v a t e the drawing c o n t r o l s discussed e a r l i e r . The user may e i t h e r draw the complete molecular diagram or modify a p r e v i o u s l y fetched s t r u c t u r e whic the new compound. The ture entry s i n c e much of the drawing o p e r a t i o n i s avoided. When the drawing i s complete, a number of a c t i o n s are performed by the host machine p r i o r to a c t u a l i n s e r t i o n of the new compound i n the database. F i r s t , an exact s t r u c t u r e search ( t a k i n g on the order of 2 seconds) i s performed over the e n t i r e database. The i n t e r n a l e x e c u t i o n format of the s t r u c t u r e search w i l l be described b r i e f l y i n the s e c t i o n on implementation. A t the u s e r s o p t i o n , the search may be performed w i t h or without regard to s t e r e o chemical d i f f e r e n c e s . A " h i t " r e s u l t i n g from the s t r u c t u r e search i n d i c a t e s that the t a r g e t compound i s , i n f a c t , not new and no r e g i s t r y takes p l a c e . "Fragmented compounds such as s a l t s , s o l v a t e s , mixtures o f two or more components, and metal c o o r d i n a t i o n complexes pose a s l i g h t l y d i f f e r e n t problem which i s based upon our t r a d i t i o n a l assignment of the same U-number to a l l s a l t s , f o r example, i n a p a r t i c u l a r s t r u c t u r a l s e r i e s , w i t h l e t t e r s u f f i x e s appended t o the U-number to d i f f e r e n t i a t e the i n d i v i d u a l s a l t s (or s o l v e n t s , or coordinated metals, e t c ) . A secondary search c a p a b i l i t y i s provided which allows the user to s e l e c t the s t r u c t u r a l subunit upon which the fragment search i s to be based. The system then r e t r i e v e s the U-numbers of a l l compounds which c o n t a i n the s e l e c ted fragment. The user can a s s i g n a r e g i s t r y number to the current compound based upon h i s examination of the r e t r i e v e d s t r u c t u r e s . To i l l u s t r a t e , a r e g i s t r y attempt on s t r u c t u r e XI i n which the c a r b o x y l a t e - c o n t a i n i n g u n i t was s p e c i f i e d as the f r a g ment of i n t e r e s t would r e t r i e v e compound XII (the r e t r i e v e d s t r u c t u r e s are d i s p l a y e d beside the o r i g i n a l s t r u c t u r e to f a c i l i t a t e v i s u a l comparison). The system a l s o converts the search fragment to an u n i o n i z e d a c i d form and would r e t r i e v e XIII. R e g i s t r y of XI then i n v o l v e s the assignment of the same base number (as XII and XIII) plus a unique s u f f i x . The r e g i s t r y of new compounds i s accompanied by the same e r r o r checks that were discussed f o r the data entry system, but 1

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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s i n c e the double entry approach i s no longer used, the v i s u a l i n s p e c t i o n of s t r u c t u r e s plays an important r o l e i n compound r e g i s try. A d d i t i o n a l features of the r e g i s t r y f a c i l i t y provide the c a p a b i l i t y f o r m o d i f i c a t i o n and d e l e t i o n of e x i s t i n g data. (b) The Query F a c i l i t y . The query f a c i l i t y provides the general user a means of o b t a i n i n g i n f o r m a t i o n from the compound database. A major goal i n the design of the user language has been to make i t simple enough f o r the inexperienced user to approach and yet powerful enough to a l l o w the more knowledgeable user to formulate complex q u e r i e s . To meet t h i s need we have designed two languages. The f i r s t language, c a l l e d the novice l a n guage, i s aimed at the inexperienced o r o c c a s i o n a l user and i s simple enough to a l l o w him to r e t r i e v e i n f o r m a t i o n without the a s s i s t a n c e of an i n f o r m a t i o n s p e c i a l i s t . At each p o i n t during the i n t e r a c t i v e d i a l o o p t i o n s . At any p o i n t a more extensive d e s c r i p t i o n of the v a r i o u s options. For pur poses of s i m p l i c i t y a l i m i t e d set of queries i s a v a i l a b l e i n novi c e mode. The second language, c a l l e d the expert language, has been designed f o r the more experienced user. I t d i f f e r s from the novi c e language i n that the user i s assumed to have a working knowledge o f the syntax and semantics of the language. Queries can be s t a t e d i n a compact manner and a f u l l e r range of requests may be s p e c i f i e d . A d d i t i o n a l l y , i t has been designed to a l l o w f u t u r e data element types and search c a p a b i l i t i e s to be i n t e g r a t e d i n t o the language i n a n a t u r a l manner. The f o l l o w i n g examples i l l u s t r a t e some of the types of queries that can be s t a t e d w i t h the expert language. SEARCH COMPOUNDS WHERE STRUCTURE = SI In t h i s example the SEARCH command i s being used to search for an exact s t r u c t u r e . In response to t h i s command the s t r u c ture drawing graphics c o n t r o l s are d i s p l a y e d and the user i s asked to draw the s t r u c t u r e . S t r u c t u r e s p e c i f i c a t i o n i s performed by means of a graphics subsystem s i m i l a r to that of the s t r u c t u r e entry system. The user has the a d d i t i o n a l o p t i o n of s p e c i f y i n g absolute c o n f i g u r a t i o n s o r l e a v i n g stereochemistry undefined. In the l a t t e r case more than a s i n g l e s t r u c t u r e match could occur. Once s t r u c t u r e input has been completed, the search i s executed and the user i s n o t i f i e d of the number of compounds that matched the t a r g e t s t r u c t u r e . The set of r e g i s t r y numbers of the matching compounds i s w r i t t e n i n t o the "search r e s u l t s f i l e " , a temporary h o l d i n g area that can be manipulated by other commands to p r i n t and d i s p l a y a s s o c i a t e d i n f o r m a t i o n , or which may be saved f o r l a t e r reference.

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SEARCH COMPOUNDS WHERE STRUCTURE > Fl OR STRUCTURE > F2 This query s p e c i f i e s a SEARCH f o r compounds that c o n t a i n a t l e a s t one of two exact s t r u c t u r a l fragments. The term "fragment" i s used here t o r e f e r t o a complete connected s t r u c t u r a l u n i t . Such a search w i l l f i n d a l l s a l t s , s o l v a t e s , and mixtures i n the database that c o n t a i n a p a r t i c u l a r component much more q u i c k l y than w i l l a general s u b s t r u c t u r e search. I n response t o the command the s t r u c t u r e drawing c o n t r o l s are d i s p l a y e d and the user i s asked t o draw the s t r u c t u r a l fragments F l and F2, i n t u r n , The search i s then performed and the r e g i s t r y numbers o f q u a l i f y i n g compounds are w r i t t e n i n t o the search r e s u l t s f i l e . I n t h i s example a d i s j u n c t i o n of the two p r e d i c a t e s i s s p e c i f i e d ; i n a d d i t i o n , general Boolean expressions i n v o l v i n g c o n j u n c t i v e and negat i o n operators may be control operation hierarchy SEARCH COMPOUNDS WHERE ENTERER IN (RCA, EN, CD) AND ENTRYDATE BETWEEN l-DEC-77 AND l-JAN-78 AND U# > U-55,000 AND STRUCTURE > SSI To q u a l i f y f o r r e t r i e v a l i n t h i s SEARCH example a compound must pass f o u r t e s t s : F i r s t , the person that entered the compound o r i g i n a l l y must have the i n i t i a l s RCA, EN, o r CD. This i s an example o f the s e t p r e d i c a t e which allows a s e t o f q u a l i f y i n g values to be l i s t e d w i t h i n a p a i r of parentheses. Second, the compound must have been entered between the two i n d i c a t e d dates. This i s an example of the range p r e d i c a t e i n which lower and upper i n c l u s i v e q u a l i f y i n g bounds are s p e c i f i e d . Next, the r e g i s t r y number must be greater than U-55,000; and f i n a l l y , the compound must c o n t a i n a s u b s t r u c t u r e . The s u b s t r u c t u r e drawing cont r o l s are d i s p l a y e d and the user draws the search t a r g e t . Subs t r u c t u r e s p e c i f i c a t i o n has elements i n common w i t h s t r u c t u r e s p e c i f i c a t i o n and, i n a d d i t i o n , provides some s p e c i a l c o n s t r u c t s f o r d e f i n i n g s u b s t r u c t u r e s . The user may i n d i c a t e v a r i a b l e subs t i t u e n t s , i n d e f i n i t e p o s i t i o n i n g of groups, and v a r i a b l e - s i z e d r i n g s and chains (14). The more complicated s u b s t r u c t u r e d e f i n i t i o n s w i l l r e q u i r e the input of both g r a p h i c a l and t e x t u a l data. DISPLAY STRUCTURE, MF WHERE ENTRYDATE = l-JAN-78 The DISPLAY command i s used t o f e t c h and d i s p l a y s e l e c t e d i n f o r m a t i o n a t the t e r m i n a l . I n t h i s case the r e g i s t r y number, s t r u c t u r e diagram, and molecular formula of a l l compounds r e g i s tered on the f i r s t day of 1978 are d i s p l a y e d . Any subset of the stored data f i e l d s may be d i s p l a y e d f o r each compound and the screen i s formatted i n the most convenient f a s h i o n f o r the f i e l d s s e l e c t e d . To see the next s c r e e n f u l l of i n f o r m a t i o n the user depresses the " r e t u r n " key; t o terminate the d i s p l a y sequence the

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STOP command i s used. The WHERE clause of the DISPLAY command i s of the same form as i n the SEARCH command and may i n c l u d e non s t r u c t u r a l data as w e l l as s t r u c t u r e and s u b s t r u c t u r e search r e quests. The SEARCH and DISPLAY commands d i f f e r i n t h a t , w h i l e both search the database, save the q u a l i f y i n g r e g i s t r y numbers, and present a " h i t count" to the user, the DISPLAY command a l s o d i s p l a y s s e l e c t e d i n f o r m a t i o n a t the t e r m i n a l f o r each compound. In a d d i t i o n , DISPLAY can operate on the s e t of r e g i s t r y numbers r e t r i e v e d by a previous search. PLOT STRUCTURE FORMAT 4 WHERE U# > U-55,000 The PLOT command i s used to produce hard copy output of s e l e c t e d i n f o r m a t i o n i n a manner analogous t o the DISPLAY command. In t h i s example a request i s made f o r r e g i s t r y numbers and s t r u c ture diagrams of compound U-55,000, p l o t t e d four e l e c t r o s t a t i c p r i n t e r / p l o t t e r ( a l l s t r u c t u r e diagrams i n t h i s pa per were produced w i t h the s t r u c t u r e p l o t f a c i l i t y ) . Both s t r u c t u r a l and n o n s t r u c t u r a l i n f o r m a t i o n can be produced together i n a v a r i e t y o f formats. SAVE FILE1 This command saves the r e g i s t r y numbers r e t r i e v e d i n the most recent search i n a f i l e named FILE1. Saved search r e s u l t s may be accessed a t a l a t e r time by any of the commands described above and may be combined w i t h other saved search r e s u l t f i l e s i n new q u e r i e s . Each user may have many saved search r e s u l t f i l e s which can be kept i n d e f i n i t e l y . (c) Implementation D e t a i l s . A l l s t r u c t u r a l and nonstruc t u r a l data w i l l be s t o r e d and r e t r i e v e d through the f a c i l i t i e s of a r e l a t i o n a l database management system (RDBMS) (15,16,17,18) w i t h the exception of s p e c i a l l y - f o r m a t t e d c o n n e c t i v i t y i n f o r m a t i o n used i n c o n j u n c t i o n w i t h the s u b s t r u c t u r e search subsystem. The r e l a t i o n a l approach provides a simple data model i n which i n f o r m a t i o n i s organized i n the form of t a b l e s . A high l e v e l query language, s i m i l a r t o the expert mode query language, f r e e s the programmer from d e a l i n g w i t h the low l e v e l p h y s i c a l storage s t r u c t u r e of the data. This "data independence" allows data s t r u c t u r e s t o be changed and i n d i c e s t o be created and destroyed to meet the changing performance requirements of the system without n e c e s s i t a t i n g program m o d i f i c a t i o n s . I n a d d i t i o n , an RDBMS w i l l s i g n i f i c a n t l y reduce the system implementation time, compared w i t h that r e q u i r e d by t r a d i t i o n a l techniques. The search request, as r e c e i v e d from the user, c o n s i s t s of three b a s i c types of search elements: n o n s t r u c t u r a l data, exact s t r u c t u r e data, and s u b s t r u c t u r e data. The syntax parser c l a s s i f i e s each element of the search request i n t o one o f the three

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c a t e g o r i e s . A search i s then performed over the database f o r each category and the r e t r i e v e d r e g i s t r y numbers are combined t o produce the f i n a l search r e s u l t . To execute the p o r t i o n of the search i n v o l v i n g only n o n s t r u c t u r a l data, such as b i o l o g i c a l o r patent i n f o r m a t i o n , the system performs a r e l a t i v e l y s t r a i g h t f o r w a r d t r a n s l a t i o n of the user's request i n t o the query language of the RDBMS, which supports a l l of the p r e d i c a t e and l o g i c c o n s t r u c t s a v a i l a b l e w i t h the expert language. The RDBMS then executes the search and r e t u r n s the set of r e g i s t r y numbers of q u a l i f y i n g compounds. The p o r t i o n of the search that i n v o l v e s exact s t r u c t u r e s and exact s t r u c t u r a l fragments i s executed i n two phases. F i r s t an 8-byte hash v a l u e i s c a l c u l a t e d from the c a n o n i c a l i z e d (10) conn e c t i o n t a b l e f o r each exact fragment and s t r u c t u r e . The query f a c i l i t y of the RDBMS i s then used to search the database f o r a l l compounds that c o n t a i n l a t e d hash v a l u e s . Next compounds are r e t r i e v e d and the r e l e v a n t a t t r i b u t e s f o r the atom and bond d e s c r i p t o r s are compared t o determine i f the s t r u c t u r e s do, i n f a c t , match the t a r g e t s t r u c t u r e . The p o r t i o n of the search which i n v o l v e s chemical s u b s t r u c tures presents more d i f f i c u l t i e s . Since a general-purpose d a t a base management system cannot be employed e f f i c i e n t l y t o perform s u b s t r u c t u r e searching (SS), a s p e c i a l approach i s r e q u i r e d . The chemical i n f o r m a t i o n l i t e r a t u r e i s r e p l e t e w i t h examples of the e f f o r t that has been d i r e c t e d toward the development of e f f i c i e n t SS a l g o r i t h m s . Good screening techniques have been developed, (19 20 21) s e t r e d u c t i o n methods have evolved, (22>23) and atomby-atom search techniques have been r e f i n e d (14> 24). More r e c e n t l y , i n c r e a s i n g a t t e n t i o n has been g i v e n t o the use of spec i a l i z e d hardware i n SS (24) and i n the c l o s e l y r e l a t e d problem of t e x t u a l database searching (25). The t r a d i t i o n a l approach to SS has been the "three phase" search. The f i r s t step i n v o l v e s some form of f u l l s t r u c t u r e screen i n which from s e v e r a l hundred to a thousand o r more p r e c a l c u l a t e d screen b i t s are used to q u i c k l y e l i m i n a t e 90 t o 99.9 percent of the s t r u c t u r e s . T h i s i s g e n e r a l l y f o l l o w e d by a step i n which candidate atoms are l o c a t e d i n the remaining s t r u c t u r e s f o r each s u b s t r u c t u r e atom; and f i n a l l y , an atom by atom mapping of the s u b s t r u c t u r e i n t o the s t r u c t u r e i s performed. We have decided to take an approach i n which s p e c i a l i z e d hardware i s employed to perform a s e q u e n t i a l scan of the database i n c o n j u n c t i o n w i t h a moderately e f f i c i e n t screen. The screening i s performed i n r e a l time by an i n t e l l i g e n t d i s k c o n t r o l l e r as the data passes the read head of the d i s k . This i s followed by a very e f f i c i e n t atom and bond candidate s e l e c t i o n step and then a f i n a l atom-by-atom match. These l a s t two steps are performed on a d e d i c a t e d minicomputer. The general component c o n f i g u r a t i o n of the SS system i s shown i n F i g u r e 7. When the search request i s r e c e i v e d by the host machine the y

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Figure 7. General hardware-component configuration of substructure-search sys tem. Front end consists of graphics minicomputers. Back end consists of dedicated minicomputer, "intelligent" disk controller, and dedicated disk.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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SS p o r t i o n s are e x t r a c t e d and sent to the SS minicomputer f o r exe c u t i o n . The SS minicomputer then sends the s u b s t r u c t u r e screen b i t s to the i n t e l l i g e n t d i s k c o n t r o l l e r and i n s t r u c t s i t to s t a r t scanning the d i s k . The s t r u c t u r e screens and connection t a b l e s w i l l be s t o r e d on the d i s k i n the format shown i n Figure 8. A ones-complement o p e r a t i o n i s performed on the s t r u c t u r e screen before i t i s w r i t t e n on the d i s k . Therefore, b i t s w i t h a value of 1 represent those s t r u c t u r a l a t t r i b u t e s that are absent i n the s t r u c t u r e . As the screen b i t s of each s t r u c t u r e pass the read head of the d i s k they are read by the c o n t r o l l e r and l o g i c a l l y AND ed w i t h che s u b s t r u c t u r e screen b i t s s u p p l i e d to the c o n t r o l l e r by the minicomputer. I f the r e s u l t of t h i s o p e r a t i o n i s nonzero the s t r u c t u r e cannot p o s s i b l y c o n t a i n the s u b s t r u c t u r e and i s e l i m i n a t e d from f u r t h e r c o n s i d e r a t i o n ; otherwise, the connect i o n t a b l e i s read i n t o the main memory of the minicomputer f o r f u r t h e r p r o c e s s i n g . Th when the end of a t r a c over to the next t r a c k . Scanning continues a f t e r a one r e v o l u t i o n delay. While the d i s k i s being scanned by the c o n t r o l l e r the minicomputer i s simultaneously executing the candidate s e l e c t i o n and atom-by-atom matching p o r t i o n s of the search. The atom and bond candidate s e l e c t i o n step i s performed by an a l g o r i t h m t h a t combines b i t screen and set r e d u c t i o n techniques. The connection t a b l e i s arranged i n a s p e c i a l format, w i t h one t a b l e entry f o r each bond i n the s t r u c t u r e . Each entry contains the atom types and sequence numbers of the atoms at each end of the bond as w e l l as the bond type. E n t r i e s are ordered by i n c r e a s i n g frequency of occurrence (based on s t a t i s t i c s c a l c u l a ted over the e n t i r e database) of the simple p a i r (atom-bond-atom sequence) c o n t a i n i n g the bond. In a d d i t i o n , a s m a l l number of screen b i t s , c a l l e d a p a i r screen, i s a s s o c i a t e d w i t h each bond. The p a i r screen, which i s a f u n c t i o n of atom and bond sequences w i t h i n a r a d i u s of 2 bond lengths of the c e n t r a l bond, d e s c r i b e s the s t r u c t u r a l environment i n the immediate neighborhood of the bond i n a manner s i m i l a r to that of a f u l l s t r u c t u r e screen. The p a i r screen b i t s are c a l c u l a t e d at the time the compound i s regi s t e r e d and are s t o r e d permanently i n the database. Although these e x t r a b i t s i n c r e a s e the s i z e of the database, experiments have shown t h a t they help provide short and r e l a t i v e l y c o n s i s t e n t search times. Execution proceeds by s e l e c t i n g , i n t u r n , each entry i n the s u b s t r u c t u r e t a b l e and screening against i t those e n t r i e s i n the s t r u c t u r e t a b l e t h a t are of the same simple p a i r type. The complemented screen b i t s of each q u a l i f y i n g s t r u c t u r e entry are l o g i c a l l y AND'ed w i t h the screen b i t s of the s u b s t r u c t u r e entry i n the same manner as f o r the f u l l s t r u c t u r e screen described above. A r e s u l t of zero i n d i c a t e s that the environment of the s e l e c t e d bond i n the s t r u c t u r e i s s i m i l a r to the environment of the current bond i n the s u b s t r u c t u r e . Candidate i n f o r m a t i o n i s s t o r e d for each s t r u c t u r e bond that matches the s u b s t r u c t u r e bond, to be f

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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l a t e r i n the f i n a l atom-by-atom mapping of the s u b s t r u c t u r e the s t r u c t u r e . I f any s u b s t r u c t u r e atom or bond f a i l s to a candidate i n the s t r u c t u r e , the examination of t h a t s t r u c i s h a l t e d (a "no match" c o n d i t i o n ) . Figure 9 shows an example of the candidate s e l e c t i o n process u t i l i z i n g a s i m p l i f i e d p a i r screen of four b i t s per bond (although the optimal number of screen b i t s has yet to be determined, i t w i l l be i n the range of e i g h t to s i x t e e n b i t s per bond), which represent an adjacent s i n g l e bond, an adjacent double bond, an attached oxygen atom, and an attached carbon atom. In t h i s case, the f o l l o w i n g occurs: the t h i r d s t r u c t u r e entry i s screened a g a i n s t the f i r s t s u b s t r u c t u r e entry (same simple p a i r type) and passes the screen; the l a s t two s t r u c t u r e e n t r i e s are screened against the second s u b s t r u c t u r e entry and only the f o u r t h s t r u c t u r e entry passes the screen; and f i n a l l y , a l l of the s t r u c t u r e ent r i e s , except the t h i r d agains thir ture entry and only th i n d i c a t e the s t r u c t u r e bonds to which each s u b s t r u c t u r e bond has been mapped. I f a s t r u c t u r e passes the candidate s e l e c t i o n s t e p , an atomby-atom mapping of the s u b s t r u c t u r e i n t o the s t r u c t u r e i s performed and the r e g i s t r y numbers of compounds t h a t q u a l i f y are r e turned to the host machine as they are found. Since the SS system has yet to be implemented i n f i n a l form, accurate SS performance data are not a v a i l a b l e ; however, time p r o j e c t i o n s , based on current d i s k technology and an already implemented SS prototype system, i n d i c a t e that most searches w i l l r e q u i r e about 30 seconds elapsed time f o r the 60,000 compound database. 4.

I n t e g r a t i o n of B i o l o g i c a l Data:

Future

Goals

Although much work s t i l l needs to be done before the compound r e g i s t r y and search system w i l l be operated on a r o u t i n e b a s i s , most of the d i f f i c u l t problems concerning chemical s t r u c t u r e handling have been overcome. In the next major phase of the proj e c t the p r i n c i p a l e f f o r t w i l l focus on " b i o l o g i c a l data", a term which encompasses a very broad range of i n f o r m a t i o n i n the f i e l d of pharmacological s t u d i e s . The b i o l o g i c a l data h a n d l i n g capabil i t i e s of the query system w i l l undergo a c o n t i n u i n g e v o l u t i o n which w i l l come about not only as new types of pharmacological data become a v a i l a b l e f o r i n c o r p o r a t i o n i n t o the system, but a l s o as the need f o r (and a v a i l a b i l i t y o f ) new techniques f o r manipul a t i n g experimental data evolves. I n i t i a l work on the i n c o r p o r a t i o n of b i o l o g i c a l i n f o r m a t i o n i n t o the compound r e g i s t r y and search system w i l l d e a l mainly w i t h data that i s already being captured on a r o u t i n e b a s i s f o r computer input and storage. This i n c l u d e s screening r e s u l t s i n which the b i o l o g i c a l response of compounds to a v a r i e t y of t e s t screens i s i n d i c a t e d by numerical a c t i v i t y values or b i n a r y a c t i v i t y assignments ( a c t i v e / i n a c t i v e ) . A d d i t i o n a l data types to be i n c o r -

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

2

4

3

1 4

Figure 9.

2

5

6

=

_

STRUCTURE TABLE S M IR PLS F IC E IR D P A I EEN B O N D A T O M # 2 A T O M # 1 C ATOM #2TYPE TYPE TYPE - = 0 ATOM #1 1 4 C 0 1111 5 4 C 0 1 001 1 3 C 0 1011 1 2 C C 1110 5 6 C C 10 10

=

Simplified candidate-selection example (this is the second phase in a substructure search)

c-c-o-c-c

II

0

STRUCTURE

1

c-c-?

II

Ο

3

SUBSTRUCTURE

SUBSTRUCTURE TABLE ATOM #1BOND ATOM #2M IR F IC E IR D ATOM #1 ATOM #2TYPE TYPE TYPE PS A IPLS EEN 2 3 C 0 -1 0C 1 = 0O 1 2 C C 1110 ? 2 4 C 1111

130

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

porated w i l l e v e n t u a l l y i n c l u d e t o x i c i t y i n f o r m a t i o n and more det a i l e d a c t i v i t y r e s u l t s that p e r t a i n to i n d i v i d u a l c l a s s e s of pharmacological agents. As was mentioned i n the s e c t i o n on implementation, searches over the b i o l o g i c a l p o r t i o n of the database w i l l be c o n t r o l l e d by the r e l a t i o n a l database management system. The l o g i c c o n s t r u c t s of the expert query language w i l l a l l o w the user to s p e c i f y r a t h e r complex chemical and b i o l o g i c a l search requests i n which, for example, the database i s searched f o r a l l compounds that cont a i n a p a r t i c u l a r s u b s t r u c t u r e , which a l s o e x h i b i t a d e s i r e d a c t i v i t y l e v e l i n a given s c r e e n , and which a l s o were submitted a f t e r a p a r t i c u l a r date. Use of the RDBMS promises not only to reduce s u b s t a n t i a l l y the e f f o r t r e q u i r e d f o r i n t e g r a t i o n of the chemical and b i o l o g i c a l databases, but a l s o w i l l s i m p l i f y cons i d e r a b l y the e v o l u t i o n of b i o l o g i c a l l y - o r i e n t e d search c a p a b i l i ties. In a d d i t i o n to p r o v i d i n of chemical and b i o l o g i c a l data ( f o r d i s p l a y or r e p o r t generation purposes), an important feature of the system w i l l be i t s a b i l i t y to c r e a t e subsets of the main database. Users w i l l be able to t r e a t the r e s u l t s of t h e i r searches as t h e i r own p r i v a t e d a t a bases which can be accessed by s p e c i a l l y t a i l o r e d a p p l i c a t i o n programs. For example, compounds which were r e t r i e v e d by a combined s u b s t r u c t u r e and screening a c t i v i t y search could become source data f o r more d e t a i l e d analyses u s i n g p a t t e r n r e c o g n i t i o n , molecular m o d e l l i n g , or s t a t i s t i c a l techniques. Although we expect that the b i o l o g i c a l i n f o r m a t i o n h a n d l i n g c a p a b i l i t i e s of the system w i l l undergo a c o n t i n u i n g e v o l u t i o n , there i s a need f o r the i n c l u s i o n of other types of data as w e l l . S p e c t r a l data, patent s t a t u s i n f o r m a t i o n , CAS r e g i s t r y numbers, chemical names, and p h y s i c a l property data a l l f a l l under the umb r e l l a of " m e d i c i n a l chemical i n f o r m a t i o n " and are some of the more important data types that have been planned f o r eventual i n c l u s i o n i n the system. The p r o j e c t e d c a p a b i l i t i e s of the system, enabling a user to i n t e r a c t i v e l y query and manipulate such d i v e r s e types of i n f o r m a t i o n , should make the system an important asset i n the research and research management f u n c t i o n s . Literature Cited 1.

2. 3. 4.

Computer-Assisted Organic Synthesis, Wipke, W. T. and Howe, W. J., e d s . , ACS Symposium S e r i e s No. 61, American Chemical S o c i e t y , Washington, D . C . (1977). Minicomputers and Large Scale Computations, Lykos, P., e d . , ACS Symposium S e r i e s No. 57 (1977). Computer-Assisted Structure Elucidation, Smith, D. H., e d . , ACS Symposium S e r i e s No. 54 (1977). Chemometrics: Theory and Application, K o w a l s k i , B. R . , e d . , ACS Symposium S e r i e s No. 52 (1977).

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

8.

HOWE AND HAGADONE

On-Line Information System

5.

131

Algorithms for Chemical Computations, C h r i s t o f f e r s o n , R. E., ed., ACS Symposium S e r i e s No. 46 (1977). 6. Computer Networking and Chemistry, Lykos, P., ed., ACS Sym posium S e r i e s No. 19 (1975). 7. Howe, W. J. and Hagadone, T. R., "Substructure S e a r c h i n g " , in Proceedings of the Technical Information Retrieval Com mittee of the Manufacturing Chemists Association, Washington Meeting, 1977, in p r e s s . 8. Corey, E . J. and Wipke, W. T., Science, 166, 178 (1969). 9. Morgan, H . L., J. Chem. Doc., 5, 107 (1965). 10. Wipke, W. T. and D y o t t , T. M., J. Amer. Chem. Soc., 96, 4834 (1974). 11. B l a k e , J. Ε., Farmer, Ν. Α . , and Haines, R. C., J. Chem. Inf. and Computer Sci., 17, 223 (1977). 12. Corey, E . J., Wipke, W. T., Cramer, R. D., and Howe, W. J., J. Amer. Chem. Soc, 13. Wipke, W. T., in Computer Chemical Information, Wipke, W. T., Heller, S. R., Feldman, R. J., Hyde, E., e d s . , p . 147, Wiley Publ., New York (1974). 14. Brown, H. D., Castlow, Μ., C u t l e r , Ε. Α . , Jr., Demott, Α. Ν., Gall, W. B., Jacobus, D. P., and Miller, C. J., J. Chem. Inf. and Computer Sci., 16, 5 (1976). 15. Codd, E . F., "A Relational Model of Data f o r Large Shared Data Banks", Commun, of the ACM, XIII, 377 (1970). 16. Codd, E . F., "Further N o r m a l i z a t i o n of the Data Base R e l a tional Model", Courant Computer Science Symposia 6, Data Base Systems, Prentice-Hall, New York (1971). 17. Date, C. J., An Introduction to database Systems, Addison Wesley, Reading, M a s s . , (1975). 18. A s t r a h a n , M. M., et al, "System R. R e l a t i o n a l Approach to Database Management", A.C.M. Transactions on Database Sys tems, 1, 97 (1976). 19. Feldman, Α . , Hodes, L., J. Chem. Doc., 15, 147 (1975). 20. Adamson, G. W., Bush, J. Α . , M c l u r e , Α . , and Lynch, M. F., J. Chem. Doc., 14, 44 (1974). 21. Meyer, Ε., "Superimposed Screens f o r the GREMAS System", i n Proc. FID-IFIP Conference, p . 280, Samuelson, Κ., ed., Rome Meeting, 1967, North Holland P u b l . (1968). 22. Sussenguth, Ε. H., Jr., J. Chem. Doc., 5, 36 (1965). 23. F i g u e r a s , J., J. Chem. Doc., 12, 237 (1972). 24. H a i n e s , R. C., "Substructure Search Design Study Status Re p o r t " , Chemical A b s t r a c t s S e r v i c e Working Paper (unpublished), 1976. 25. Bird, R. M., Tu, J. C., Worthy, R. Μ., "Associative/Parallel Processors for Searching Very Large Textual Data Bases", SIGIR-SIGARCH-SIGMOD T h i r d Workshop on Computer A r c h i t e c t u r e for Non-numeric P r o c e s s i n g , McGill, M. J., ed., SIGMOD, 9, No. 2, 8 (1977). RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9

Warner-Lambert/Parke-Davis-CAS

Registry III

Integrated I n f o r m a t i o n System ROGER D. WESTLAND, RAYMOND L. HOLCOMB, JOHN W. VINSON, JON D. STEELE, ROBERT J. CARDWELL, ROBERT L. SCOTT, THOMAS D. HARKAWAY, PATRICIA J. HYTTINEN, and TINA WILLIAMS Warner-Lambert/Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105 In 1946 the Parke-Davi h Laboratories c e n t r a l i z e d chemical and biological storage and retrieval. These were e f f e c t i v e until the l a t e 1950's, when manual methods were g r a d u a l l y r e i n f o r c e d w i t h punched card files. By the mid 1960's, machine readable data files were a v a i l a b l e f o r everything except a complete chemical s t r u c t u r e and certain other s t r u c t u r e - r e l a t e d i n f o r m a t i o n . Throughout the development o f computerized i n f o r m a t i o n systems it has been necessary to m a i n t a i n redundant manual files until n e a r l y all i n f o r m a t i o n is computer-readable. Only now, a f t e r adding chemical s t r u c t u r e s to the computer database can we b e g i n to abandon the manual files maintained f o r over 30 y e a r s . I n a d d i t i o n to s t r u c t u r e - h a n d l i n g capability, we have developed a system to link sample i n v e n t o r y and p r o p e r t i e s , b i o l o g i c a l screening d a t a , and research document data to produce reports and answers to q u e r i e s , both interactively and in batch mode. In c o n s i d e r i n g approaches to computerized chemical s t r u c t u r e p r o c e s s i n g (I, 2, 3), we accepted an o f f e r by Chemical A b s t r a c t s S e r v i c e (CAS) to e s t a b l i s h under c o n t r a c t a p r i v a t e s a t e l l i t e o f the CAS R e g i s t r y System (4) which employs over 640 programming modules and over a q u a r t e r - m i l l i o n source statements. Since Warner-Lambert/Parke-Davis (WL/PD) had compatible hardware f o r both p r o c e s s i n g and s t r u c t u r e p r i n t i n g , we were i n a p o s i t i o n to take advantage o f CAS s l a r g e investment i n h i g h q u a l i t y graphics, name p r o c e s s i n g , and computer e d i t s . CAS offered an advanced and h i g h l y developed system which could be i n s t a l l e d i n a short time at r e l a t i v e l y low c o s t . Ongoing development at CAS to enhance the system f o r s t o r i n g , r e t r i e v i n g , and r e p o r t i n g the w o r l d ' s chemical l i t e r a t u r e made c o m p a t i b i l i t y w i t h CAS a t t r a c t i v e . Current use o f CAS s s e r v i c e i n Europe (j>) , Japan ( 6 ) , and the United States (7., 8, 9) evidences i n c r e a s i n g r e l i a n c e on the CAS R e g i s t r y System and suggests the p o s s i b i l i t y o f broad i n d u s t r i a l and governmental use i n the f u t u r e . A p i l o t p r o j e c t at WL/PD r e q u i r e d l e s s than two-man months of e f f o r t to implement CAS*s s t r u c t u r e - p r i n t i n g algorithms from 1

1

0-8412-0465-9/78/47-084-132$05.00 Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9.

WESTLAND

E TAL.

Integrated

Information

System

133

the CAS G r a p h i c a l Data S t r u c t u r e (10, JL1, 12) r e c o r d . Success o f the experiment i n p l o t t i n g s t r u c t u r e s o f the type shown i n F i g u r e 1 s t i m u l a t e d f u r t h e r e x p l o r a t i o n which u l t i m a t e l y l e d to the development o f a WL/PD - CAS i n t e g r a t e d system f o r s t o r i n g , r e t r i e v i n g , manipulating, and r e p o r t i n g chemical and b i o l o g i c a l research data. System Design With an INQUIRE® (Infodata Systems Inc., F a l l s Church, V i r g i n i a ) database management system a v a i l a b l e on our IBM 370/168 computer, h i s t o r i c a l computer f i l e s o f sample i n v e n t o r y and t r a n s a c t i o n s , p h y s i c a l and chemical p r o p e r t i e s , b i o l o g i c a l screening data, research document data, and other miscellaneous f i l e s were converted to INQUIRE f i l e format (13), and stored on d i s k (Figure 2 ) . Sampl storage) and i n v e n t o r y c e n t r a l computer an o n - l i n e balance and a keyboard-CRT t e r m i n a l . Other WL/PD i n f o r m a t i o n i s entered i n a k e y - t o - d i s k o p e r a t i o n using the ENTREX® (14) system, thereby p r o v i d i n g options f o r d i r e c t entry o f data from l a b o r a t o r i e s , when a p p r o p r i a t e . Output from the P r i v a t e R e g i s t r y f i l e s a t CAS i s converted by means o f update programs t o INQUIRE f i l e formats. M u l t i - f i l e searching o f the INQUIRE f i l e s f o r ad hoc queries o r r e p o r t c o n s t r u c t i o n can be done e i t h e r i n t e r a c t i v e l y w i t h TSO terminals o r i n batch mode using a V a r i a n V74 computer as a HASP w o r k - s t a t i o n . Generic s t r u c t u r e searches o f the computer f i l e o f fragment-coded s t r u c t u r e s g i v e as o p t i o n a l output punched paper tape that cont r o l s the d i s p l a y o f s t r u c t u r e images on m i c r o f i c h e . The coded m i c r o f i c h e c o n t a i n i n g 196 s t r u c t u r e images a t 24X r e d u c t i o n are stored i n the c a r o u s e l o f a storage and r e t r i e v a l u n i t manufactured by Image Systems, Inc. Since a new s u b s t r u c t u r e search system f o r the WL/PD f i l e w i l l not be usable u n t i l the e n t i r e backlog o f s t r u c t u r e s has been entered i n t o the P r i v a t e R e g i s t r y , we are cons i d e r i n g programs to a l g o r i t h m i c a l l y generate the Parke-Davis Fragmentation Code (15) from CAS connection t a b l e s . This w i l l a l l o w us to continue using our present search techniques i n the interim. P r o p e r t i e s F i l e . The f o l l o w i n g data are i n c l u d e d i n the keyt o - d i s k entry o f p r o p e r t i e s : a c c e s s i o n number, source, percent of parent component, m e l t i n g o r b o i l i n g p o i n t , s p e c i a l handling or storage requirements, p h y s i c a l s t a t e , s o l u b i l i t y , s t a b i l i t y , s e l e c t e d a n a l y t i c a l and s p e c t r a l data, sample weight and l o c a t i o n , submission date, and l i t e r a t u r e r e f e r e n c e s . Transactions F i l e . A M e t t l e r Model PT320 balance having BCD output, and a CRT t e r m i n a l are i n t e r f a c e d w i t h the c e n t r a l computer through a microprocessor and the V a r i a n HASP w o r k - s t a t i o n . At the time sample weights are a u t o m a t i c a l l y recorded, the

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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134

O F MEDICINAL

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operator keys 1) t r a n s a c t i o n type, 2) a c c e s s i o n number, 3) date, 4) whether the sample i s being r e c e i v e d and from whom, o r being t r a n s m i t t e d and to whom, and 5) storage l o c a t i o n . While t h i s i n f o r m a t i o n i s s t o r e d i n the " T r a n s a c t i o n s " database a running record o f the amount o f sample on hand i s c a l c u l a t e d from onl i n e balance e n t r i e s and s t o r e d i n the " P r o p e r t i e s " database. B i o l o g y F i l e . Screening data from b i o l o g y l a b o r a t o r i e s a r e recorded on data e n t r y forms a p p r o p r i a t e l y coded (13) f o r key-tod i s k h a n d l i n g , e i t h e r i n a c e n t r a l l o c a t i o n o r the l a b o r a t o r y itself. R e s u l t forms are customized f o r each t e s t and a r e rearranged i n t o a standard format by the ENTREX processor before being sent to the main computer. Document F i l e . Search parameters o f i n t e r n a l l y generated r e s e a r c h r e p o r t s are i n c l u d e (word) p r o c e s s i n g equipment inexpensive r e c o r d i n g o f s e l e c t e d t e x t such as a b s t r a c t s . A v a r i e t y o f o p t i o n s to INQUIRE i n c l u d e techniques which can index and r e t r i e v e on the b a s i s o f such t e x t . The m u l t i - f i l e o p t i o n allows s e l e c t e d records t o be combined w i t h data from other INQUIRE f i l e s . CAS F i l e s . Machine p r o c e s s i n g o f data must be performed a t CAS to take advantage o f the many machine v a l i d a t i n g and d u p l i cate checking f e a t u r e s o f the CAS R e g i s t r y System. Although s t r u c t u r e s and chemical names could be entered a t the user's l o c a t i o n followed by t r a n s m i t t a l o f computer-readable data t o CAS f o r p r o c e s s i n g , CAS s keyboarding conventions and h i g h volume a l l o w them to o f f e r the s e r v i c e a t a cheaper r a t e than we could match i n t e r n a l l y . A c c o r d i n g l y , data sheets o f chemical s t r u c t u r e s and names are shipped to CAS on a twice-weekly b a s i s ( F i g u r e 3). A t CAS the hand-written i n f o r m a t i o n i s checked and e d i t e d , and s t r u c t u r e s , s t e r e o - d e s c r i p t o r s , and names are entered by a k e y - t o - d i s k procedure (17) . Keyboarded records o f s t r u c tures are processed i n the P r i v a t e R e g i s t r y s a t e l l i t e system w i t h the use o f most o f the computer e d i t s o f the CAS R e g i s t r y System (17). A d i s t i n g u i s h i n g f e a t u r e o f t h i s process i s a check t o determine i f the newly entered s t r u c t u r e a l s o e x i s t s i n the R e g i s t r y f i l e o f over four m i l l i o n substances. I f an exact d u p l i cate i s found i n the CAS f i l e , the CAS R e g i s t r y Number along w i t h the CA Index name and synonyms are returned as an update t o the WL/PD Names F i l e . C r i t i c a l to the d u p l i c a t e check as c u r r e n t l y handled i s that the e n t i r e s t r u c t u r e , i n c l u d i n g the s a l t or s o l vate p o r t i o n , must be i d e n t i c a l even as to the p r o p o r t i o n o f components o f a multi-component s t r u c t u r e (e.g., RNI^'I^SC^ does not match RNH2*1/2H2S04. System m o d i f i c a t i o n s could remove the l i m i t a t i o n . A p r o f i l e o f a l l WL/PD substances entered i n t o the p r i v a t e WL/PD system i s maintained by CAS and checked p e r i o d i c a l l y f o r matches i n the CAS R e g i s t r y f i l e s . Therefore, w i t h i n 1

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

WESTLAND E T AL.

Integrated Information System

OH

Figure 1. Plotted structure of chalcomycin (CAS Registry Number 20283-48-1). Stereochemistry is provided by a "text descriptor" which is printed along with the topological representation shown. DOCUMENTS

BIOLOGY

BIOLOGY

INVENTORY INQUIRE DATABASES

DATA ENTRY

BIODATA

PROPERTIES f

CONVERSION <_\ PROGRAMS

"\i

• DOCUMENTS • INVENTORY TRANSACTIONS - PROPERTIES • NAMES

INVENTORY-TRANSACTIONS

C

• GRAPHICS

ON-LINE BALANCE

TSO TERMINALS

MULTI-FILE QUERIES

DATA FROM CAS

' CONNECTION TABLES

Q

UPDATE PROGRAMS

> MISCELLANEOUS

INQUIRE COMMAND LANGUAGE

PL/I PROGRAMS

I CONSOLIDATED REPORTS INCLUDE STRUCTURES

Figure 2. Information flow CAS

STRUCTURES I + NAMES

REGISTRY

nr

L

I ONE-WAY FLOW

MAIL \ VERIFICATION /

PRIVATE

WL/PD

REGISTRY

PROFILE

STANDARD DISTRIBUTION / ^ ~ ^ \ FORMAT (SDF) +

/

\

GRAPHICS (GDS)

V

L

+ NAMES

V

I TO WL/PD

Figure 3.

CAS processing

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL O F MEDICINAL CHEMICAL INFORMATION

136

l i m i t s o f the d u p l i c a t e i d e n t i f i c a t i o n system, the novelty o f compounds i n the WL/PD f i l e i s known and the i n f o r m a t i o n i s kept current. The CAS R e g i s t r y f i l e s , w i t h compounds published s i n c e 1965, undoubtedly c o n t a i n a large f r a c t i o n of the compounds c h a r a c t e r i z e d throughout the h i s t o r y o f chemistry. In a d d i t i o n to the f u l l s t r u c t u r e search and the high q u a l i t y s t r u c t u r e p r i n t i n g c a p a b i l i t y o f the system, the CAS f i l e s and computer programs i n use by WL/PD provide a s t r a i g h t f o r w a r d way o f p r i n t i n g a t WL/PD systematic names using the many s p e c i a l characters f a m i l i a r to chemists (4). A f t e r keyboarding the WL/PD s t r u c t u r e s and names a t CAS, the f o l l o w i n g data sets are produced by means of the p r i v a t e R e g i s t r y for d e l i v e r y to WL/PD: -

Connection tables Structure displa CA names WL/PD names E d i t i n g Records

CAS F i l e s a t WL/PD. From the CAS data sets generated f o r WL/PD compounds, the f o l l o w i n g computer databases are produced: - A "Substance" database, which i d e n t i f i e s the unique substances r e g i s t e r e d and the fragment components and proportions - A "Fragments" database, which c a r r i e s connection t a b l e s , i n t e r n a l r e g i s t r y numbers and other s t r u c t u r a l data - A "Names" database w i t h a l l systematic (CAS and WL/PD) names and synonyms - A "GDS" ( f o r G r a p h i c a l Data Structure) (12) database which holds i n vector form two-dimensional representations which may be drawn by v a r i o u s p l o t t i n g d e v i c e s . F i l e s are shipped on a r e g u l a r schedule from CAS to WL/PD, and processed, using update programs, to produce the INQUIRE databases. Report Generation. The INQUIRE system has a very f l e x i b l e set o f report generation c a p a b i l i t i e s . The m u l t i - f i l e o p t i o n allows a report to be generated from s e v e r a l databases a t once: i n f o r m a t i o n such as b i o l o g i c a l screening data, chemical and p h y s i c a l p r o p e r t i e s , t r a n s a c t i o n h i s t o r y , and existence of research documents can be drawn together i n one r e p o r t . INQUIRE a l s o allows the formation o f output i n t o t a b l e s , l i s t i n g s w i t h headings and comments, and decoded f i e l d s which permit a compact code i n the database to be expanded to more readable forms. The chemical s t r u c t u r e and name can a l s o be combined w i t h the text o f the INQUIRE r e p o r t . Programs have been w r i t t e n to format the g r a p h i c a l s t r u c t u r e , the expanded character set name,

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9.

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137

and the t e x t o f the query i n t o a s i n g l e p l o t , which can be output on the STATUS e l e c t r o s t a t i c p l o t t e r . These p l o t s can be copied onto e i t h e r paper o r card stock by XEROX r e d u c t i o n copying t o provide both f i l e cards and f u l l - p a g e r e p o r t s . Information from f i v e d i f f e r e n t computer f i l e s a r e combined to provide chemical s t r u c t u r e , name, p r o p e r t i e s , source, other compound-specific i n f o r m a t i o n , and b i o l o g i c a l screening r e s u l t s shown i n F i g u r e 4. Routine queries can a l s o be executed by using the "macro" f e a t u r e o f INQUIRE. Macros a r e sets o f INQUIRE commands s t o r e d on the computer, and can be invoked by r e f e r r i n g t o the name o f the macro. Thus, complicated m u l t i f i l e searches and r e p o r t s can be generated w i t h only very simple i n p u t . System S e c u r i t y . The t a k i n g o f c o n f i d e n t i a l i n f o r m a t i o n out of manual o f f i c e f i l e s the r i s k o f d i s c l o s u r a decade o f s u c c e s s f u l experience i n handling the N a t i o n a l Cancer I n s t i t u t e ' s c o n f i d e n t i a l f i l e s a t t e s t s t o the adequacy o f CAS p r e c a u t i o n s . We hope that advancing technology o f computer s e c u r i t y w i l l keep pace w i t h the i n c r e a s i n g use o f the computer f o r i n f o r m a t i o n systems. Hardware C o n f i g u r a t i o n The c e n t r a l computer a t the Research L a b o r a t o r i e s i n Ann Arbor i s a V a r i a n V74, which a l s o acts as a HASP w o r k - s t a t i o n to the corporate 370/168 i n M o r r i s P l a i n s , New Jersey. The V a r i a n supports a f u l l complement o f p e r i p h e r a l equipment i n c l u d i n g l i n e p r i n t e r s , d i s k s , and tape d r i v e s (see F i g u r e 5 ) . The STATOS e l e c t r o s t a t i c p l o t t e r allows t e x t and graphics to be composed simultaneously on l i n e - p r i n t e r - s i z e pages. The Entrex-data-entry system has replaced keypunches f o r most p r o d u c t i o n work. When data have been entered, v a l i d a t e d , and c o r r e c t e d , they may be sent on to the V74 (or through i t t o the 370) f o r f u r t h e r p r o c e s s i n g . Data communications between M o r r i s P l a i n s and Ann Arbor i s managed by a p a i r o f Codex communications m u l t i p l e x o r s . These d e v i c e s , a t e i t h e r end o f a s i n g l e 9600 baud leased l i n e , s p l i t i t s c a p a c i t y between the V74 and 13 independent Trendwriter TSO t e r m i n a l s . Because a l l components a r e l i n k e d together a t some p o i n t , the e n t i r e o p e r a t i o n i s very f l e x i b l e . A user may debug a query a t a TSO t e r m i n a l , g e t t i n g sample p r i n t o u t s i n t e r a c t i v e l y . When the r e p o r t i s s a t i s f a c t o r y , a background search may be executed to process an e n t i r e f i l e . The r e s u l t s , when they a r r i v e a t the V74, may be p r i n t e d , held f o r f u r t h e r p r o c e s s i n g , or p l o t t e d on the STATOS i f s t r u c t u r e s a r e i n c l u d e d . The TSO user may continue w i t h another query w h i l e background p r o c e s s i n g i s underway.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL O F MEDICINAL CHEMICAL INFORMATION

138

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9.

WESTLAND E T AL.

Integrated Information System

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL C H E M I C A L INFORMATION

140

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9. WESTLAND E T A L .

Integrated Information System

141

Future Developments C o m p a t i b i l i t y w i t h the R e g i s t r y System i s a t t r a c t i v e because c o n t i n u i n g developments a t CAS make the world's chemical l i t e r a ture more a c c e s s i b l e . R e g i s t r y Numbers obtained d u r i n g processing p o t e n t i a l l y provide a d i r e c t l i n k to a b s t r a c t s . L i n k s t o data i n a b s t r a c t s by means o f s u b s t r u c t u r e search o f the e n t i r e CAS s t r u c t u r e f i l e i s a s i g n i f i c a n t p r o j e c t r e c e n t l y begun a t CAS (18). Conversion o f systematic nomenclature to c o n n e c t i o n t a b l e s i s now used as a computer e d i t i n the CAS R e g i s t r y system, and the reverse process o f generating names from c o n n e c t i o n t a b l e s i s being i n v e s t i g a t e d (19). Standardized storage and r e t r i e v a l o f chemical i n f o r m a t i o n can lead to s i g n i f i c a n t c o l l a b o r a t i v e e f f o r t not o n l y f o r search systems which CAS i s e x p l o r i n g , but a l s o f o r other areas such as r e a c t i o n codes, computer a s s i s t e d s y n t h e s i s analysis. Further enhancements t o the hardware w i l l probably c e n t e r around some s o r t o f i n t e r a c t i v e graphics d e v i c e . T h i s w i l l i n t r o d u c e another l e v e l o f hardware, s i n c e a s m a l l computer w i l l be used t o pre- and post-process the g r a p h i c a l data f o r e f f i ciency. Summary Chemical A b s t r a c t s S e r v i c e ' s (CAS) R e g i s t r y I I I records o f chemical s t r u c t u r e are used t o augment Warner-Lambert/ParkeD a v i s computer f i l e s o f chemical and b i o l o g i c a l data. The marriage provides a r e l a t i v e l y low-cost system having uncommon p o t e n t i a l . Key-to-disk e n t r y a t WL/PD o f chemical p r o p e r t i e s , b i o l o g i c a l r e s u l t s , and other i n f o r m a t i o n and " o n - l i n e " weighing at WL/PD o f samples are p a r a l l e l e d by k e y - t o - d i s k e n t r y a t CAS o f chemical s t r u c t u r e s and names. Computer-readable chemical s t r u c ture records are returned from CAS to WL/PD. INQUIRE database management o f f i l e s a t WL/PD provides i n t e r a c t i v e o r b a t c h m u l t i f i l e search c a p a b i l i t y and r o u t i n e g e n e r a t i o n o f r e p o r t s . Batch p r o c e s s i n g a t WL/PD i s used f o r s u b s t r u c t u r e s e a r c h i n g and, u s i n g CAS systems i n s t a l l e d a t WL/PD, f o r h i g h q u a l i t y p r i n t i n g of s t r u c t u r e s and names. WL/PD substances are checked f o r d u p l i c a t i o n i n the CAS R e g i s t r y S t r u c t u r e f i l e o f over f o u r m i l l i o n substances a t the time o f r e g i s t r a t i o n and p e r i o d i c a l l y t h e r e a f t e r . CAS provides R e g i s t r y Numbers and systematic names and synonyms f o r detected d u p l i c a t e s . C o m p a t i b i l i t y w i t h CAS o f f e r s the p o s s i b i l i t y 1) f o r e a s i e r access to computer-readable a b s t r a c t s , 2) f o r s u b s t r u c t u r e searching o f the e n t i r e CAS database, and 3) f o r a l g o r i t h m i c g e n e r a t i o n o f systematic names from connection t a b l e s . 1

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

142 Acknowledgement

We are indebted to Mr. N . A . Farmer, Dr. D. C. Myers, Mr. T. J . Walker, Mr. C. E. Watson, and Mr. R. J . Zalac of CAS, and to Mr. F. C. Fensch, Mr. S. Fine, and Dr. A . M. Moore of WL/PD for their encouragement, advice, and many valuable discussions.

Literature Cited 1.

Lynch, M. F., Harrison, J. M., Town, W. G., and Ash, J. E . , "Computer Handling of Chemical Structure Information", American Elsevier, New York, Ν. Y., 1971. 2. Wipke, W. T., Heller, S. R., Feldmann, R. J., and Hyde, E . , "Computer Representation and Manipulation of Chemical Information", Wiley, New York, Ν. Y., 1974. 3. Ash, J. E. and Hyde Wiley, New York, Ν 4. Dittman, P. G., Stobaugh, R. E . , and Watson, C. E . , "The Chemical Abstracts Service Chemical Registry System. I. General Design", J. Chem. Inf. Comput. Sci., (1976), 16, 111-121. 5. Schenk, H. R. and Wegmüller, F., "Substructure Search by Means of the Chemical Abstracts Service Chemical Registry II System", J. Chem. Inf. Comput. Sci., (1976), 16, 153-161. 6. "Agreement Links CAS, Japanese Organization", CAS Report, Number 6, September 1977. 7. Seals, J. V., Jr., Watson, C. E . , and Wilson, G. Α., "National Cancer Institute's Drug Research and Development Chemical Information System: Operation in the CAS Environ ment", Abstracts, 169th National Meeting of the American Chemical Society, Philadelphia, Pa., April 1975. 8. Milne, G. W. A. and Heller, S. R., "The NIH EPA Chemical Information System", Abstracts, 175th National Meeting of the American Chemical Society, Anaheim, Calif., March 1978. 9. McNulty, P. J., Garton, C. R., Buckley, S. L . , Raezer, T. W., Cohen, S. G., Kippenhan, Ν. Α., Dyott, Τ. Μ., and Gilbert, J. T., "Agricultural Chemicals Computerized Infor mation System at Rohm and Haas Company", Abstracts, 173rd National Meeting of the American Chemical Society, New Orleans, La., March 1977. 10. Farmer, N. A. and Schehr, J. C., "A Computer-Based System for Input, Storage, and Photocomposition of Graphical Data", Proc. Assoc. Comput. Mach.. (1974), 2, 563. 11. Dittman, P. G., Mockus, J., and Couvreur, Κ. M., "An Algo rithmic Computer Graphics Program for Generating Chemical Structure Diagrams", J. Chem. Inf. Comput. Sci., (1977), 17, 186-192.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9.

12.

13.

14. 15. 16. 17. 18.

19.

WESTLAND ET AL.

Integrated Information System

143

Blake, J. E . , Farmer, Ν. Α., and Haines, R. C., "An Inter active Computer Graphics System for Processing Chemical Structure Diagrams", J . Chem. Inf. Comput. Sci., (1977), 17, 223-228. Stein, J. D., Jr., Delaney, F. M., Peluso, S. D., and Starker, L. N., "A Computer-Based Comprehensive Bio-Data Information Retrieval System", J. Chem. Doc., (1973), 13, 145-152. ENTREX, Inc., Burlington, Mass., a Nixdorf Company. Geer, H. Α., Moore, A. M., Howard, C. D., and Eady, C. E . , "The Parke-Davis Code for Chemical Structures", J. Chem. Doc., (1962), 2, 110-113. Stein, J. D., Jr. and MacDougall, Ε. E . , The Warner-Lambert Company, Morris Plains, New Jersey, personal communication, 1977. Dayton, D. L. and Service Chemical Registr Editing", J. Chem. Inf. Comput. Sci., (1976), 16, 219-222. Farmer, N. A. and Weisgerber, D. W., "A New Strategy for Substructure Searching", Chemical Abstracts Service Open Forum, 174th National Meeting of the American Chemical Society, Chicago, Illinois, August 1977. Vander Stouw, G. G., "Computer Programs for Editing and Validation of Chemical Names", J. Chem. Inf. Comput. Sci., (1975), 15, 232-236.

RECEIVED

August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

10 The N I H / E P A Chemical Information System STEPHEN R. H E L L E R Environmental Protection Agency, PM-218, Washington, DC 20460 G. W. A. MILNE National Institutes of Health, Bethesda, MD 20014

Over the past seven years, NIH and EPA have developed a computer based Chemica line interactive compute cological data (1). The CIS consists mainly of a collection of numeric (as opposed to bibliographic) data bases and software to search these data bases. The four main areas of the CIS can be grouped as follows: 1. Searchable numeric data bases 2. Structure and Nomenclature Search system (SANSS) 3. Chemical Substance Information System (CSIS) 4. Analysis and Modelling Programs The first three areas w i l l be described, with emphasis on the linking of areas 1 and 2. Figure 1 shows how the four areas of the CIS are coordinated, with the Structure and Nomenclature Search System (SANSS) in the center. At present there are 25 data bases in the SANSS. These comprise the CIS Unified Data Base (UDB) and are searchable by the SANSS (2). They are shown in Figure 2. The referral aspects of the CIS represent a valuable tool for scientific and administrative work both within our respective Agencies as well as outside these Agencies, in the public and private sector, here in the USA and abroad. The referral capability of the CIS consists of a list of data bases, literature references (e.g., Merck Index) and Government Regulatory files, which can all be accessed simultaneously by consulting a single central file. A l l the available information concerning a substance can be located in a single operation. As the number of data bases is increased, the CIS becomes more valuable and a time-saving device in searches for chemical information. Typical questions that can be readily and inexpensively answered by this approach are: * Has this chemical been sold as a pesticide in the USA? * Is there a measured acute toxicity value for a particular air pollutant? * Is information concerning a drug taken in overdose quantities and identified by gas chromatography-mass spectrometry in the Merck Index or the NIMH book on psychotropic drugs? * Has a certain chemical been registered for sale in the USA? This chapter not subject to U.S. copyright. Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978. WATER DROP

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RETRIEVAL

O F MEDICINAL CHEMICAL INFORMATION

NUMBER OF COMPOUNDS

FILE NIH/EPA-MSSS C-13 N M R

25,560 3,765

E P A - A C T I V E I N G R E D I E N T S IN P E S T I C I D E S PESTICIDES S T A N D A R D S ORD —CHEMICA OIL A N D H A Z A R D O U AEROS/SAROAD AEROS/SOTDAT STORET C H E M I C A L SPILLS T S C A I N V E N T O R Y C A N D I D A T E LIST NIMH-PSYCHOTROPIC

DRUGS

S R I - P H S LIST 149 O F C A R C I N O G E N S N B S — S I N G L E C R Y S T A L FILE H E A T S O F F O R M A T I O N O F G A S E O U S IONS G A S - P H A S E P R O T O N AFFINITIES N S F - R A N N P O L L U T A N T FILE FDA-PESTICIDE

REFERENCE STANDARDS

CPSC-CHEMRIC

MONOGRAPHS

CAMBRIDGE

UNIVERSITY

CRYSTAL DATA

1,454 384

65 572 234 577 33,579 1,686 4,448 18,362 3,169 454 225 613 1,000 10,018

EROICA T H E R M O D Y N A M I C D A T A

4,492

M E R C K INDEX

8,894

ITC — I N T E R N A T I O N A L T R A D E C O M M I S S I O N

9,194

N I O S H - R E G I S T R Y OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES N F P A - H A Z A R D O U S CHEMICALS

19,908 397

Figure 2. List of the current 25 collections which currently comprise the CIS unified data base (integrated SANSS data base 3/1/78)

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

10.

HELLER AND MILNE

NIH/EPA

Chemical Information System

147

Among the data bases being added t o the CIS t h i s year are those shown i n Figure 3. Over the next 2-3 years, w i t h the cont i n u e d a d d i t i o n o f f i l e s that are e i t h e r generated or used by the Government, i t i s expected that the l i s t of r e f e r r a l f i l e s w i l l grow to over 250. With the recent e f f o r t s of the four main F e d e r a l r e g u l a t o r y Agencies (EPA, FDA, CPSC, OSHA) to coordinate t h e i r v a r i o u s a c t i v i t i e s , such as the study and r e g u l a t i o n of s p e c i f i c chemicals, t h i s c e n t r a l r e f e r r a l system takes on more importance. This four-Agency group, known as the Interagency Regulatory Liason Group (IRLG) ( 3 ) , i s now working to use the Chemical A b s t r a c t s Servic e (CAS) R e g i s t r y Number as the standard chemical i d e n t i f i e r f o r the chemicals i n a l l the four Agencies. An i n t e r n a l r e g u l a t i o n has been proposed which w i l l make t h i s mandatory. The r e g u l a t i o n i s modelled a f t e r EPA Order 2800.2, c u r r e n t l y the o n l y Government r e g u l a t i o n to mandate standardized chemical c l a s s i f i c a t i o Over the past fou been submitted t o CAS, under c o n t r a c t t o EPA, t o o b t a i n the CAS R e g i s t r y Numbers f o r these chemicals. The r e s u l t o f t h i s massive and c o s t l y e f f o r t i s the CIS U n i f i e d Data Base (UDB) of about 101,000 unique chemicals a s s o c i a t e d w i t h the 25 f i l e s shown i n F i g u r e 2. That there i s so much overlap of the chemicals found i n these f i l e s i s not s u r p r i s i n g . I t i s beginning to appear that there are r e l a t i v e l y few chemicals which are a c t u a l l y studied i n any d e t a i l , and even fewer that become s i g n i f i c a n t i n commerce, as, f o r example, drugs, food a d d i t i v e s or p e s t i c i d e s . P r o j e c t i o n s suggest that by the time the CAS r e g i s t r a t i o n process o f some 250 f i l e s i s completed, the a c t u a l s i z e o f the CIS u n i f i e d Data Base w i l l not exceed 175,000-200,000 substances. The need then w i l l be to o b t a i n as much u s e f u l and accurate i n f o r m a t i o n about these substances as i s necessary to p r o t e c t h e a l t h and environment i n the USA, as i s r e q u i r e d by the missions o f our r e s p e c t i v e Agencies. I t i s our hope that by d e f i n i n g the s i z e o r scope of the " r e a l " universe o f chemicals, that the burden on i n d u s t r y w i l l be lessened and that f u t u r e e f f o r t s w i l l be e a s i e r to d i r e c t . Thus, we see l i t t l e immediate need t o study the universe that CAS has d e f i n e d , of over some 4,000,000 chemicals found i n the l i t e r a t u r e that CAS has a b s t r a c t e d s i n c e 1965. Only about 12% of these four m i l l i o n have appeared more than once i n the CASa b s t r a c t e d l i t e r a t u r e and probably no more than 3% are produced and s o l d i n anything but research q u a n t i t i e s . S t r u c t u r e and Nomenclature Search System (SANSS) The S t r u c t u r e and Nomenclature Search System (SANSS), the heart o f the CIS, i s based upon the work of Feldraann who developed the o r i g i n a l search algorithms a number o f years ago (5). A d d i t i o n of a nomenclature search program, an i d e n t i t y search program and a search program based on the Edgewood CIDS s t r u c t u r e keys ( 6 ) , as w e l l as some c o n s i d e r a b l e refinement of the system

American Chemical Society Library 1155 16th St. N. W. In Retrieval ofWashington, Medicinal Chemical Information; D. C. 20036Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL C H E M I C A L INFORMATION

U.S. Coastguard Chemical Properties File. E P A I E R L Non-Criteria Pollutant Emissions. E P A , Section 111A of the Clean A i r Act. E P A , Office of Air Quality, Permissible Standards, Criteria Pollutants. E P A , Office of Water Supply File of Drinking Water Pollutants. E P A , Pollutant Strategies Branch, Selected Organic A i r Pollutants. E P A , Effluent Guidelines Consent Decree List E P A , Section 112 of the Clean Air Act. E P A , O R D , Gulf Breeze, List of Chemicals. E P A , Carcinogen Assessment G r o u p List of Chemicals.

E P A , List of Potentially Hazardous Chemicals f r o m Coal and O i l . California O S H A List of Chemical Contaminants. W H O , F o o d and Agriculture Organization, List of Pesticides. E P A , I E R L , Organic Chemicals in Air

Carcinogens. N C T R , Potential Industrial Carcinogens and Mutagens. E P A , I E R L , List of Environmental Carcinogens. E P A , OPP, Pesticide Literature Searches. N I E H S , Laboratory Chemicals. T o x i c and Hazardous Industrial Chemicals Safety Manual. International Technical Information Institute, T o k y o .

E P A , R P A R Candidates Chemical Review Schedule List.

List of Teratogenic Chemicals. Medical Information Center, Karolinska Institute, Stockholm.

E P A , O T S Status Assessments.

E P A , List of Hazardous Pesticides.

E P A , Standing Air Monitoring Work Group List of N o n Criteria Pollutants.

E P A , Mutagenicity Studies. C I T T , List of Candidates.

EPA, O R D - O H E E Chemicals.

E P A , T S C A Section 8e, List of Chemicals.

Figure 3.

Laboratory

Newfilesbeing added to the NIH/EPA CIS UDB in Spring, 1978

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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has been c a r r i e d out over the l a s t few years. The SANSS and i t s data base, connection t a b l e s from CAS and chemical names, has absorbed the bulk o f the CIS budget. C u r r e n t l y , the SANSS can be used i n a number o f ways. The more important methods a r e : * Nomenclature Search (NPROBE) * Ring Search (RPROBE) * Fragment search (FPROBE) * CIDS code search (SPROBE) * Molecular weight search (MW) * Molecular formula search (MF) * Substructure search (SUBSS) * F u l l s t r u c t u r e search (IDENT) In a d d i t i o n t o these searching programs, there are a number o f r e t r i e v a l and d i s p l a y o p t i o n s a v a i l a b l e i n the system. These include: * Displa * D i s p l a y of CAS C o l l e c t i v e Index names * D i s p l a y of synonyms, common names and trade names * D i s p l a y of molecular formulas * D i s p l a y of f i l e s c o n t a i n i n g a substance * R e t r i e v a l based upon CAS R e g i s t r y Number The f o l l o w i n g s e c t i o n s w i l l be devoted to e x p l a i n i n g the v a r i o u s SANSS nodules and g i v i n g examples o f how they can be used. At the end o f the chapter an example o f the i n t e r f a c i n g of the SANSS w i t h the NIOSH RTECS data base o f acute t o x i c i t y data (7) w i l l be des c r i b e d , as an example of the d i r e c t i o n that CIS development i s t a k i n g . Since there i s c o n s i d e r a b l e i n t e r e s t on the part o f the chemical i n d u s t r y i n the implementation o f TSCA, access t o the b u l k of the p u b l i c data t h a t EPA w i l l be u s i n g i n i t s work f o r a d m i n i s t e r i n g TSCA should be of v a l u e . At present, development of the SANSS i s being d i r e c t e d towards the immediate needs of EPA s O f f i c e o f Toxic Substance (OTS), so that the foundation t h a t has been b u i l t f o r the SANSS can be used most e f f e c t i v e l y f o r the implementation of TSCA. 1

Name - Nomenclature Search (NPROBE) The name search, NPROBE, has been implemented as a r e s u l t of requests expressed by both the SANSS user community and the CEQTSCA MITRE study proposal (8) f o r the development o f a Chemical S t r u c t u r e and Nomenclature System which we have c a l l e d the S t r u c t u r e and Nomenclature Search System. The software used i s s i m i l a r t o t h a t used i n the ÇHEMLINE system a t the N a t i o n a l L i b r a r y o f Medicine (NLM) and a l l o w s f o r complete or p a r t i a l (fragment) name search. There are an average o f s l i g h t l y over 3 names per chemical i n CIS UDB, as opposed t o s l i g h t l y more than 2 names per chemical i n CHEMLINE ( 9 ) . The CHEMLINE f i l e , which l i n k s p r i m a r i l y t o the TOXLINE l i t e r a t u r e r e f e r e n c e s , i s made up

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

150

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mostly of r e s e a r c h chemicals, and thus i s not l i k e l y to have the m u l t i p l e synonyms t h a t are a s s o c i a t e d w i t h commercial chemicals. In the CIS UDB, which i s comprised of f i l e s from p r i m a r i l y regu l a t o r y , and hence commercial, sources, there are the expected a d d i t i o n a l names a s s o c i a t e d w i t h m a t e r i a l s i n commerce. To conduct a nomenclature search, the user simply enters a chemical name or name fragment, as shown i n F i g u r e 4. The example shown i n F i g u r e 4 i s of a search f o r any substance i n the UDB whose name contains the fragment "DDT . From F i g u r e 4 i t can be seen that there are 12 such substances i n the UDB, of which the f i r s t , p,p DDT, i s shown i n the F i g u r e . In a d d i t i o n , a l s o shown i n t h i s f i g u r e a r e a l l the f i l e s of the UDB which c o n t a i n i n f o r mation on p,p DDT, w i t h the l o c a l f i l e i d e n t i f i e r numbers l i s t e d so that one may go d i r e c t l y to the p a r t i c u l a r f i l e and get the i n f o r m a t i o n t h a t i s contained i n that f i l e regarding ρ,ρ' DDT. I n F i g u r e 5, a name searc on the e n t i r e UDB and f i v these f i v e i s shown i n F i g u r e 5, w i t h the names of the f i l e s that have i n f o r m a t i o n about LSD. Not s u r p r i s i n g l y , the f i l e s i n c l u d e the NIMH L i s t of Psychotropic Drugs, the Merck Index and the NIOSH acute t o x i c i t y data base, as w e l l as the NIH/EPA Mass S p e c t r a l Data Base and the TSCA Candidate L i s t . There i s l i t t l e doubt t h a t the i n c l u s i o n on the TSCA Candidate or "Strawman * l i s t w i l l be changed once the f i n a l TSCA i n v e n t o r y i s p u b l i s h e d , s i n c e under present law, LSD i s an i l l e g a l chemical substance. This i s a use f u l search technique, but r e q u i r e s a l a r g e l i s t o f synonyms, a c o r r e c t s p e l l i n g , and a knowledge of how chemical names a r e broken down. For example, i n searching f o r a cyclohexanedione, i f the f i l e name o f the substance i s w r i t t e n as 2,5-cyclohexanedione r a t h e r than cyclohexan-2,5-dione, a search f o r "dione w i l l not f i n d the chemical. 11

T

f

1

11

F u n c t i o n a l Group - CIDS Key Search (SPROB) The best way t o search f o r f u n c t i o n a l groups o r s t r u c t u r e f e a t u r e s i n the CIS SANSS i s to use the Chemical Information Data Systems (CIDS) keys, developed by Edgewood A r s e n a l . The CIDS keys, a few o f which are shown i n F i g u r e 6, are the b a s i s o f a r a p i d and e f f i c i e n t way to search the CIS UDB f o r substances c o n t a i n i n g a p a r t i c u l a r f u n c t i o n a l group or s t r u c t u r e f e a t u r e . Many of the CIDS keys are q u i t e s p e c i f i c i n nature, as can be seen i n F i g u r e 6. Others, shown towards the bottom of F i g u r e 6, a r e q u i t e generic i n nature. For example, the CIDS key FG25 r e f e r s to the presence of a n i t r i l e or cyanide group i n the molecule. An example o f a CIDS key search i s given i n F i g u r e 7, where a search i s shown f o r a l l c y c l o h e x y l (SCN49) morpholine (SCN35) compounds i n the NIOSH RTECS data base of acute t o x i c i t y . There are o n l y two such compounds i n the data base, and the f i r s t o f these i s p r i n t e d out i n the f i g u r e , along w i t h i t s l o c a l NIOSH RTECS i d e n t i f i e r numbers i n d i c a t e d .

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER

AND MILNE

OPTION?

NIH/EPA

Chemical

Information

System

NPROBE

FRAGMENT OR WHOLE NAME SEARCH (F/W) (F) ? F S P E C I F Y F R A G M E N T (CR T O EXIT): D D T FILE 1, 12 C O M P O U N D S H A V I N G F R A G M E N T : D D T S P E C I F Y F R A G M E N T (CR T O EXIT): _ OPTION? SSHOW 1 HOW M A N Y S T R U C T U R E S (E T O E X I T ) ? 1_ TYPE Ε T O TERMINATE DISPLAY STRUCTURE 1 C A S R E G I S T R Y N U M B E R 50-29-3 T S C A C A N D I D A T E LIST: R000-2373 CIS M A S S S P E C T R O M E T R Y CIS C A R B O N 13 N M R S P E C T R O M E T R Y :

50-29-3.01

EPA PESTICIDES - A C T I V E INGREDIENTS: EPA OHM/TADS:

CAMBRIDGE XRAY CRYSTAL: MERCK

29201

72T16510 50-29-3.01

INDEX

EPA PESTICIDES - A N A L Y T I C A E P A S T O R E T : 39317, 39373, 39371,39374, 39372, 39370, 39359, 39375 39376, 39378, 39290, 39358, 39377, 39302, 39303, 39304, 39300, 39301 EPA C H E M I C A L SPILLS CPCSCHEMRIC F D A / E P A PESTICIDES R E F . S T A N D A R D S : 200 U.S. I N T E R N A T I O N A L T R A D E C O M M I S S I O N N B S X R A Y C R Y S T A L : 50-29-3.01 N S F C H E M I C A L S LIST: 138 PHS-149 C A R C I N O G E N S : A0240 NIOSH RTECS: KJ33250 C14H9C15

C

CL*C

C

C

C

C

C**CL

C** **C**C

C

#

C

CL*C**CL

C

CL Benzene, 1, 1, — ( 2 , 2, 2-trichloroethylidene) bis [ 4 - c h l o r o - (9CI) Ethane, 1, 1, 1-trichloro-2, 2-bis (p-chlorophenyl)— (8CI) .alpha., .alpha. —Bis (p-chlorophenyl)—.beta., .beta., .beta, -trichlorethane p, p' -Dichlorodiphenyltrichloroethane p, p' - D D T

Figure 4.

NPROBE

name search for name fragment "DDT*

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

O F MEDICINAL

OPTION? N P R O B E F R A G M E N T O R W H O L E N A M E S E A R C H (F/W) (F) ?F S P E C I F Y F R A G M E N T (CR T O E X I T ) : LSD FILE 5, 5 COMPOUNDS HAVING FRAGMENT: S P E C I F Y F R A G M E N T (CR T O E X I T ) : _ O P T I O N ? SSHOW 5 HOW M A N Y S T R U C T U R E S (E T O EXIT) ? 1 TYPE Ε TO TERMINATE DISPLAY STRUCTURE 1 C A S R E G I S T R Y N U M B E R 50-37-3 T S C A C A N D I D A T E LIST: R000-3157 CIS M A S S S P E C T R O M E T R Y MERCK INDEX NIMH P S Y C H O T R O P I NIOSH R T E C S : KE42000,KE41000,KE4375

CHEMICAL

INFORMATION

LSD

C20H25N30

C. .C

N**C

*

c. .c

* C++C

C++C •

*

•

•

*

*

C**C

ο

c

+

•

+

•

C**C *N**C**C #

N**C

Ergoline-8-carboxamide, 9, 10-dtdehydro-N, N-diethyl-6-methyl—, (8.beta.) (9CI) Ergoline-8 .beta, -carboxamide, 9, 10-didehydro-N, N-diethyl-6-methyl- (8CI) (+) - L S D D—LYsergic acid diethylamide D—Lysergic acid Ν , Ν-diethylamide

Figure 5. NPROBE name search for LSD

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER AND M I L N E

Key

NIH/EPA

Chemical

Information

System

Structure

SCN 1

SCN 35

0 Ο

FG 219

o = p —ο —

Figure6.

Sample CIDS key codes

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

153

154

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CHEMICAL

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OPTION? S P R O B E S P E C I F Y S T R U C T U R A L F E A T U R E C O D E A N D P E R M I S S I B L E M U L T I P L I C I T Y LIMITS N E X T S F C = SCN49 FOUND 428 C O M P O U N D S H A V I N G 1 OR M O R E O C C U R R E N C E S O F SCN49

N E X T S F C = SCN35 FOUND 277 C O M P O U N D

NEXT SFC = _ F I L E = 11, OPTION?

2 COMPOUNDS CONTAIN A L L

2 CODES

SSHOW 11

HOW M A N Y S T R U C T U R E S (E T O E X I T ) ? 1 T Y P E Ε T O T E R M I N A T E DISPLAY STRUCTURE 1 C A S R E G I S T R Y N U M B E R 6425-41-8 N I O S H R T E C S : QE06400,QE06700 C10H19NO C

C

C

C

Morpholine, 4 - c y c l o h e x y l Cyclohexylmorpholine N-Cyclohexylmorpholine 4-Cyclohexylmorpholine

Figure 7.

(8CI9CI)

CIDS key search for cyclohexyl morpholine compounds

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

10.

HELLER AND MILNE

NIH/EPA

Chemical

Information

System

155

M o l e c u l a r Weight (MW) and Formula (MF) Search In a d d i t i o n to searching f o r a p a r t i c u l a r f u n c t i o n a l group using the CIDS keys as shown above, i t i s p o s s i b l e to search f o r a compound, or a group of compounds, u s i n g molecular weight. The molecular weight search, shown i n F i g u r e 8, a l l o w s f o r e i t h e r a s p e c i f i c molecular weight, o r , as i s i n d i c a t e d i n the f i g u r e , a range o f molecular weights. In the p a r t i c u l a r example shown i n F i g u r e 8, the Merck Index i s being searched f o r a l l occurrences of compounds w i t h a molecular weight between 368 and 380. There are 167 such substances as can be seen i n the top p a r t of F i g u r e 8. T h i s i s too l a r g e a number and so i t was decided to t r y t o narrow or f i l t e r the search down to a smaller number u s i n g a molecular formula search. In t h i s case what was r e a l l y sought were a l l compounds which have two oxygen atoms and a molecular weight between 368 and formula (02) i s shown, o p e r a t i o n (INTERsect) between the f i l e of 167 compounds w i t h the c o r r e c t molecular weight range and the f i l e of 1484 having the c o r r e c t p a r t i a l formula. The r e s u l t of t h i s AND o p e r a t i o n i s a f i l e c o n t a i n i n g the 16 compounds i n the Merck Index which have a molecular weight between 368 and 380 as w e l l as e x a c t l y two oxygen atoms i n the molecule. A t the bottom of F i g u r e 8, the f i r s t of the 16 answers i s p r i n t e d o u t . T h i s compound, w i t h a molecular formula o f C21.H23.C1F.N.02 and a molecular weight of 375, i s H a l o p e r i d o l , which i s a drug used as a s e d a t i v e and t r a n q u i l i z e r . In the event t h a t there i s no i n t e r e s t i n c h l o r i n a t e d compounds, even though they may meet the molecular weight and molecular formula c r i t e r i a , a f u r t h e r molecular formula search may be conducted, as shown i n F i g u r e 9, f o r compounds w i t h 1-4 c h l o r i n e atoms. From F i g u r e 9, i t can be seen that there are 986 compounds w i t h 1-4 c h l o r i n e atoms i n the Merck Index f i l e . Since the requirement was f o r compounds t h a t d i d not c o n t a i n t h i s halogen atom, a Boolean NOT o p e r a t i o n between the 986 c h l o r i n e c o n t a i n i n g compounds and the 16 compounds p r e v i o u s l y found i s performed, as seen i n the center of F i g u r e 9. This r e s u l t s i n the removal o f three of the s i x t e e n substances, and o f the remaining t h i r t e e n , the f i r s t one, Androsta-3,5-dien-17-ol, 3-(cyclopentyloxy)-17-methyl-, (17.beta.), i s p r i n t e d out and shown a t the bottom of F i g u r e 9. T h i s , o f course, l i k e the other twelve i n the f i l e , does not c o n t a i n the c h l o r i n e that was present i n three of the answers to the f i r s t search shown i n F i g u r e 8. The a b i l i t y to i n t e r a c t and impose v a r i o u s l i m i t a t i o n s and f i l t e r s on searching i s a very powerful c a p a b i l i t y of the SANSS.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

O F MEDICINAL

CHEMICAL

INFORMATION

OPTION? ^ TYPE MW OR RANGE, CR TO EXIT USER: 368-380 FILE = 4, 167 COMPOUNDS WITH MW 368-380 OPTION? MF CR TO EXIT, COMPLETE (C), PARTIAL (P), OR RANGED (R) MF? USER:£ THE NUMBER OF ATOM TYPES IS: J _ ENTER ATOM, FOLLOWED BY COUNT FOR EACH TYPE, E.G. C6. TYPE 1 IS: 02 FILE = 5, 1484 COMPOUNDS HAVING PARTIAL MF: 02

CR TO EXIT, COMPLETE (C), PARTIAL (P), OR RANGED (R) MF? USER: OPTION? INTER 4 5 FILE = 6 RESULTING SOURCE FILES WERE: 4 OPTION? SSHOW 6 HOW MANY STRUCTURES (E TO EXIT) ? J _ TYPE Ε TO TERMINATE DISPLAY STRUCTURE 1 C A S REGISTRY NUMBER 52-86-8 MERCK INDEX C21H23CIFN02 CL

C

c

c

C

C

c

F

C

C - Ο

C

C **C" C

1-Butanone, 4-(4-(4-chlorophenyl) -4-hydroxy-1-piperidinyl]-1-(4-fluoro phenyl)- (9CI)

Figure 8. Molecufor-weight range search

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER

ANDMILNE

NIH/EPA

Chemical

Information

System

OPTION? MF CR TO EXIT, COMPLETE (C), PARTIAL (P), OR RANGED (R) MF? USER: R THE NUMBER OF ATOM TYPES IS: 1 ENTER ATOM, FOLLOWED BY RANGE FOR EACH TYPE, E.G. C6,12. TYPE 1 IS: CL1 4 FILE = 7, 1&6 COMPOUNDS HAVING PARTIAL MF IN RANGE: CL1-4

OPTION? NOT 6 7 FILE = 8 RESULTING REFERENCE SOURCE FILES WERE: 6 OPTION? SSHOW 8 HOW MANY STRUCTURES (E TO EXIT) ? 5. TYPE Ε TO TERMINATE DISPLAY STRUCTURE 1 CAS REGISTRY NUMBER 67-81-2 MERCK INDEX

C25H3802

C ·· Ο

C

C ** C

0««C««C

C

C

C

C

C

C

C

Androsta-3,5-dien-17-ol, 3-(cyclopentyloxy)-17-methyl-, (17.beta.)- (9 CI)

Figure 9.

Sample of combination searches of MF, MW

with NOT logic

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

158

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MEDICINAL

CHEMICAL

INFORMATION

Nucleus - Ring Search (RPROBE) One of the f e a t u r e s of the CIS SANSS that has made the system u s e f u l i s the s t r u c t u r e of the f i l e w i t h respect to r i n g systems. The SANSS has a h i e r a r c h i c a l f i l e s t r u c t u r e that a l l o w s f o r r a p i d and inexpensive searching f o r s p e c i f i c r i n g s or r i n g systems. In F i g u r e 10, a l i s t of some of the commands used to generate s t r u c t u r e s are given. To show how the SANSS works and how one can use the v a r i o u s query modules, the remainder of the chapter w i l l be devoted to searching through the NIOSH TTECS data base f o r chemic a l s having an aromatic r i n g , s u b s t i t u t e d on ortho carbons w i t h c h l o r i n e and bromine r e s p e c t i v e l y . The f i r s t t h i n g that must be done i n order to perform such a search i s to b u i l d the 'query s t r u c t u r e that i s to be sought. This i s done w i t h the f i r s t few commands shown i n F i g u r e 11. The query s t r u c t u r e i n Figure 11 i s a c h l o r o bromo (ortho) probe search w i l l be conducte matic r i n g , s i n c e i t does not take i n t o account the nature of the s u b s t i t u e n t s . A l s o , s i n c e other s u b s t i t u e n t s on the benzene r i n g w i l l be p e r m i t t e d , i t i s necessary to r e s e t the s u b s t i t u e n t search l e v e l from EXACT (only two s u b s t i t u e n t s and these must be ortho) to 'IMBED (there must be two ortho s u b s t i t u e n t s at a minimum). The command to do t h i s i s EXIM, which i s short f o r EXact/lMbed s w i t c h . The search shown i n Figure 11 r e v e a l s that there are 2715 compounds i n the NIOSH RTECS f i l e that c o n t a i n at l e a s t t h i s r i n g p a t t e r n . To f i l t e r such p o t e n t i a l l y broad responses f u r t h e r , one can use CIDS keys searches and other such c o n s t r a i n t s as shown below. 1

1

1

1

Fragment Search (FPROBE) One f e a t u r e necessary to any s t r u c t u r e search system i s the a b i l i t y to search f o r atom-centered fragments. In a fragment search the user must s p e c i f y an atom and i t s neighbors. The exact (or g e n e r i c ) nature of the bonds between t h i s c e n t r a l atom and each of i t s neighbors i s then entered and a search i s conducted for a l l occurrences of such a fragment. I f a query s t r u c t u r e has already been generated, as was done i n F i g u r e 11, that s t r u c t u r e can be used by the SANSS program to generate and search f o r f r a g ments. There are u s u a l l y a number of atoms i n a query s t r u c t u r e that can be considered as c e n t r a l to a fragment. Hence, a request for a fragment probe of the s u b s t r u c t u r e shown i n F i g u r e 11 would l e a d to searches f o r s i x fragments, four of which would be the same ( i . e . atom centered fragments about atoms 3, 4, 5 and 6 are a l l the same, r e p r e s e n t i n g a carbon atom i n an aromatic r i n g attached to two other aromatic carbon atoms i n the r i n g and a hydrogen). Such fragments are not very s p e c i f i c , and so i t i s best to i d e n t i f y the atom centered fragment f o r which one wishes to search. In F i g u r e 12, atom number 1 i s s e l e c t e d and a search for a l l occurrences of a c h l o r i n e atom on an aromatic r i n g i s

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER

AND MILNE

NIH/EPA

Chemical

COMMAND

Information

System

EFFECT

A A T O M n1 m l

Insert an atom between atom n1 and atom m l .

A B O N D n1 m l

Insert a bond between n1 and m l .

A B R A N 11 at n1

A d d a branch of length 11 at atom n1.

A L I N K n1 11 m l

Insert a chain of length 11 between

A L T B D n1 m l

Define alternate bonds in the smallest

n1 and m l . ring containing n1 and m l as aromatic A R I N G n1 m l 11 and m l . CHAIN I

Create a chain of I atoms.

CLEAR

Erase the existing query structure.

C R I N G n1 11

Create a ring of 11 atoms including

DATOM η1

Delete atom η 1.

atom n1. D B O N D n1 m l

Delete the bond joining nl and m l .

MORGA

Renumber the query structure by the

NUC66

Create a structure of two fused

REG

Retrieve the structure corresponding

R EST

Negate the effect of the previous

RIΝ G I

Create a ring of I atoms.

S A T O M n1

Define the elemental nature of atom n1.

S B O N D n1 m l

Define the nature of the bond joining

S P I R O n1 11

Create a spiro-attached ring of

WISBD n1 m l

Define alternate bonds in the smallest

Morgan algorithm. six-membered rings. to a specific registry number. command.

n1 and m l . (11 +1) atoms at n1. ring containing η 1 and m l as double bonds.

Figure 10. Commands used to generate structures for searching

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

ENTER NEW SELECTION

O F MEDICINAL

(H F O R HELP):

CHEMICAL

INFORMATION

32

C O L L E C T I O N S E L E C T E D : 32 OPTION? OPTION? RING OPTION? A B R A N 1 AT 1 1 AT 2 OPTION? S A T O M 7 SPECIFY E L E M E N T S Y M B O L =C L OPTION? S A T O M 8 SPECIFY E L E M E N T S Y M B O L = BR OPTION? A L T B D 1 2 OPTION? D 3..4

8BR2

5

1 . . 6 ? ? 7CL OPTION? EXIM SPECIFY S E A R C H L E V E L S T O B EC H A N G E D LEVELS = 4 OPTION? RPROBE C??C ? ? ? ? C

C?? ?

? ?

c??c

?

CONDITIONS O F S E A R C H CHARACTERISTICS T O B E MATCHED TYPE OF MATCH TYPE O F RING O R N U C L E U S EXACT NO HETEROATOMS EXACT SUBSTITUENTS A T 1 2 IMBED T H I S R I N G / N U C L E U S O C C U R S IN 2 7 1 5 COMPOUNDS FILE =

1,

2715

Figure 11.

COMPOUNDS C O N T A I N THIS

A ring-probe (RPROBE) benzene

RING/NUCLEUS

search for a disubstituted

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

10.

HELLER AND MILNE

NIH/EPA

Chemical

Information

System

161

performed. The r e s u l t of t h i s search i s a f i l e c o n t a i n i n g a l l 1618 compounds i n the NIOSH RTECS f i l e that c o n t a i n t h i s p a r t i c u l a r s t r u c t u r e fragment. A f t e r the fragment search i s conducted f o r the c h l o r o aromatic fragment, a s i m i l a r search i s performed on the fragment centered about atom 2, which contains a bromo s u b s t i t u e n t . This fragment probe (FPROBE) search, shown i n F i g u r e 13, r e s u l t s i n 229 occurrences of t h i s fragment i n compounds i n the NIOSH RTECS data base. Substructure Search (SUBSS) The Substructure Search o p t i o n i s an atom-by-atom, bond-bybond comparison between connection t a b l e s i n the data base and the connection t a b l e s corresponding to the query s t r u c t u r e . This time consuming, s e q u e n t i a l searc probe, fragment probe, are used as screens to speed up the process and reduce the c o s t . F o l l o w i n g the three separate searches done i n F i g u r e s 11-13, the next step i s to see which compounds i n the NIOSH RTECS data base c o n t a i n occurrences of a l l three. This i s done by a simple Boolean AND l o g i c combination of the three l i s t s of R e g i s t r y Numbers generated by the searches i n these F i g u r e s . The i n t e r s e c t i o n of the l i s t s , performed by the INTER command as shown i n F i g u r e 14, r e s u l t s i n 12 compounds meeting the c r i t e r i a of a l l three searches. However, not n e c e s s a r i l y a l l o f the 12 answers are p r e c i s e l y what i s wanted. This i s because the three searches i n F i g u r e s 11-13 are f o r " p i e c e s " of the s t r u c t u r e sought but the searches do not r e q u i r e these p i e c e s to be i n the same j u x t a p o s i t i o n as i n the query s t r u c t u r e . That i s , the three r e q u i r e ments comprise a necessary, but not s u f f i c i e n t c o n d i t i o n f o r an answer to the o r i g i n a l question. To secure an exact answer as to how many ( i f any) o f these 12 compounds meet the exact query s t r u c t u r e , i t i s necessary to perform a t r u e s u b s t r u c t u r e search (SUBSS) as i s shown i n F i g u r e 14. The r e s u l t o f the use of SUBSS shows t h a t only 7 o f 12 "answers" from the i n t e r s e c t i o n o f the three searches do have the bromine and c h l o r i n e ortho to one another on the benzene r i n g . Of the 7 answers, one i s shown i n F i g u r e 15. As i t turns out from i n s p e c t i o n of a l l 12 p r i o r answers (not shown h e r e ) , the other compounds r e t r i e v e d are meta s u b s t i t u t e d c h l o r o bromo aromatic compounds. Complete S t r u c t u r e Search (IDENT) The f i n a l SANSS module to be d e s c r i b e d i n t h i s chapter i s the search f o r a t o t a l or f u l l s t r u c t u r e , r a t h e r than a subs t r u c t u r e . T h i s module was designed p r i m a r i l y f o r the purpose of searching f o r and r e p o r t i n g s p e c i f i c chemicals as p a r t of the TSCA i n v e n t o r y r e p o r t i n g procedures. The f u l l s t r u c t u r e search, c a l l e d IDENT ( f o r IDENTity), has and w i l l continue to have

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

OPTION?

O F MEDICINAL

CHEMICAL

INFORMATION

FPROBE 1

TYPE Ε T O EXIT F R O M A L L SEARCHES, Τ TO PROCEED T O NEXT FRAGMENT SEARCH FRAGMENT: 7CL????1C

6C

2C R E Q U I R E D O C C U R R E N C E S F O R HIT : 1 T H I S F R A G M E N T O C C U R S IN 1618 C O M P O U N D S F I L E = 2,

1618

COMPOUNDS C O N T A I N THIS F R A G M E N T

Figure 12. A fragment probe (FPROBE) atom attached

OPTION?

for a chlorine

FPROBE 2

TYPE Ε T O EXIT FROM A L L SEARCHES, Τ TO PROCEED TO NEXT FRAGMENT SEARCH FRAGMENT: 8BR????2C

1C

3C R E Q U I R E D O C C U R R E N C E S F O R HIT : 1 T H I S F R A G M E N T O C C U R S IN 229 C O M P O U N D S F I L E = 3,

229 C O M P O U N D S C O N T A I N T H I S F R A G M E N T

Figure 13. A fragment probe (FPROBE) for a bro mine atom attached to an aromatic carbon atom

OPTION?

INTER

FILE = 4 , SOURCE

1

2

FILES WERE:

OPTION?

3

RESULTING REFERENCES = SUBSSS

1

2

12

3

4

DOING SUB-STRUCTURE

SEARCH

T Y P E Ε T O EXIT FILE ITEM 10 S T R U C T U R E B E I N G S E A R C H E D HITS S O F A R 6 FILE = 5 ,

Figure 14.

SUCCESSFUL

SUB STRUCTURES

=

21609905

7

Intersection and substructure search of files de rived in Figures 11-13

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER

AND MILNE

STRUCTURE NIOSH R T E C S :

NIH/EPA

Chemical

7 CAS REGISTRY NUMBER TE70000

Information

System

4824-78-6

C10H12BrC12O3PS

CL * *

C * *

ο

C..C

* * C*****0**P++S * *

BR C #

C..C • * CL

ο * * C * C

Phosphorothioic acid, 0-(4-bromo-2, 5-dichlorophenyl) 0 , 0 — d i e t h y l ester (8CI9CI) Bromophos-ethyl Ethyl bromophos Filariol 60 Nexagan G

Figure 15.

One of seven substructure search hits

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

164

RETRIEVAL

O F MEDICINAL

CHEMICAL

INFORMATION

s p e c i f i c a p p l i c a t i o n t o TSCA a c t i v i t i e s . For example, a f t e r the f i n a l "grandfather i n v e n t o r y r e q u i r e d under s e c t i o n 8 of the Act i s p u b l i s h e d and made a v a i l a b l e , v i a the CIS, as w e l l as by other means, i t w i l l be necessary f o r p o t e n t i a l vendors o f a chemical t o determine i f the chemical they wish t o see o r manuf a c t u r e i s i n the Inventory and can thus be produced and marketed without e x t e n s i v e pre-manufacturing t e s t i n g . Use o f the IDENT search w i l l q u i c k l y r e v e a l i f the chemical i s i n the TSCA i n ventory. Of course, one can use the name search c a p a b i l i t i e s , but there i s no guarantee t h a t the name used by the manufacturer w i l l be i n the l i s t o f synonyms a s s o c i a t e d w i t h the i n v e n t o r y . The s t r u c t u r e shown i n F i g u r e 16 was generated u s i n g the standard SANSS s t r u c t u r e generation commands, such as those l i s t e d i n F i g u r e 10. The IDENT search was then invoked and a f t e r being t o l d that the s t r u c t u r e had the normal number of hydrogen atoms, cons i s t e n t w i t h normal v a l e n c e UDB. The s t r u c t u r e wa i d e n t i f i e r i n f o r m a t i o n , as w e l l as a number o f synonyms, one of which i s the TSCA C l e r i c a l Code Designation number f o r the substance. 11

SANSS-Data Base I n t e r f a c e s A s t r u c t u r e or a nomenclature search i s g e n e r a l l y only a means t o an end. The end i s o f t e n some data a s s o c i a t e d w i t h the s t r u c t u r e s found. In order t o f a c i l i t a t e r e t r i e v a l o f such i n f o r m a t i o n , an i n t e r f a c e between the CIS numeric data bases and the SANSS has been constructed. This a l l o w s f o r a search through the UDB f o l l o w e d by a data search (or r e t r i e v a l ) and permits one to answer such queries a s : * Do any ortho bromo-chloro aromatic compounds have a t o x i c i t y greater than 1.0 mg./kg? In the example shown i n Figure 17, the f i r s t three answers from the previous search are used to r e t r i e v e the t o x i c i t y data a s s o c i a t e d w i t h these compounds. The automatic i n t e r f a c e between the systems i s invoked by the command TSHOW and then the previous f i l e o f 7 CAS R e g i s t r y Numbers, generated by SUBSSS, are s p e c i f i e d , w i t h only the f i r s t three being p r i n t e d out upon request. Summary The NIH/EPA CIS has developed to the p o i n t where complex questions can be readilyanswered. The a b i l i t y to manipulate s t r u c t u r e and numeric data and e s t a b l i s h c o r r e l a t i o n s between the two should be o f c o n s i d e r a b l e value t o the EPA i n i t s work under the Toxic Substances C o n t r o l A c t , as w e l l as to s c i e n t i s t s i n g e n e r a l . The value o f the SANSS l i n k e d t o CNMR data has been r e c e n t l y shown (10), and no doubt other s t r u c t u r e - d a t a s t u d i e s

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

HELLER AND MILNE

OPTION?

NIH/EPA

Chemical

Information

System

ρ

10CL

70

?

+

?

+

8CL3??1??2P?50?11 ?

?

?

?

?

?

9 C L 4 0 60 ? ? 12 OPTION? TOTAL

IDENT

PROTON COUNT (P F O R P R O G R A M

TOTAL

F O R THIS S T R U C T U R E ESTIMATE)

PROTON COUNT BASED

:

IS

Ρ

UPON N O R M A L CONDITIONS

IS

8

ARE THERE A N Y ABNORMA WOULD

A F F E C T THI

PROTON COUNT FILE

FOR NOD

1 0 , T H I S S T R U C T U R E IS C O N T A I N E D

OPTION?

IN

1 COMPOUNDS.

S S H O W 10

STRUCTURE

1 CAS REGISTRY

TSCA CANDIDATE EPA PESTICIDES

-

EPA OHM/TADS:

CAMBRIDGE MERCK

LIST:

NUMBER

52-68-6

R001-5032

ACTIVE

INGREDIENTS:

57901

72T16519

XRAY

CRYSTAL:

52-68-6.01

INDEX

EPA PESTICIDES

-

EPA CHEMICAL

SPILLS

FDA/EPA

A N A L Y T I C A L R E F .STNDS.:

PESTICIDES

R E F .S T A N D A R D S :

PHS-149 C A R C I N O G E N S : NIOSH RTECS:

6780

48

C0147

TA07000 C4H8C1304P

CL

Ο

*

+

*

+

CL*C**C**P *0**C #

*

» CL

«

#

#

#

Ο

Ο

C Phosphonic acid,

(2, 2, 2-trichloro-1-hydroxyethyl)-,

dimethyl ester

(8C

I9CI) Agroforotox Anthon Bayer L

13/59

Chlorofos

Figure 16.

Example of IDENT

search for a complete molecule

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

166

RETRIEVAL

D A T A B A S E IS NOW

O F MEDICINAL

CHEMICAL

INFORMATION

RTECS

OPTION? R E T R I E V E N U M B E R I N G S Y S T E M ? CAS SOURCE? FILE 5 T H E R E WERE 7 D I S P L A Y HOW M A N Y ? (TYPE Ε T O EXIT) 3 CAS N U M B E R = 2104963 NIOSH N U M B E R = TE71750 O R L - R A T LD50: 1600 MG/K T F X : T X A P A 9 14,515,69 SKN-RBT LD50: 720 MG/K T F X : G U C H A Z 6.54,73 U N K - M A M LD50: 2000 MG/K T F X : 30ZDA9 -,335,71 Phosphorothioic acid, O — (4-bromo-2, 5-dichlorophenyl) O, O-dim ethyl ester (3CI9CI) C8H8BrC1203PS

CAS N U M B E R = 2720174 NIOSH N U M B E R = TB01850 O R L - R A T LD50: 35 MG/K TFX: A R S I M * 20,6,66 O R L - M U S LD50: 77 MG/K T F X : A R S I M * 20,6,66 Phosphonothioic acid, e t h y l - , 0-(4-bromo-2, 5-dichlorophenyl) O-ethyl ester (8CI9CI) C10H12BrC12O2PS

CAS NUMBER = 2720185 NIOSH N U M B E R = TB10700 O R L - R A T LD50: 73 MG/K T F X : A R S I M * 20,6,66 Phosphonothioic acid, methyl—, O—(4-bromo-2, 5-dichlorophenyl O-O-methylethyl) ester (9CI) C10H12BrC12O2PS Figure 17.

Example of NIOSH RTECS

toxicity data retrieval

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

10.

HELLER AND MILNE

NIH/EPA Chemical Information System

w i l l be undertaken now that the necessary groundwork has been laid. Acknowled gement s The authors wish to thank the f o l l o w i n g for t h e i r help and cooperation i n developing the CIS SANSS: R. J . Feldmann, W. G r e e n s t r e e t , M. Yaguda, M. Bracken, A . F e i n , G. Marquart, and J. Miller. Literature Cited 1. 2.

3. lished 4. 5. 6.

7.

8.

9. 10.

H e l l e r , S . R . , M i l n e , G.W.A., and Feldmann, R.J., Science, (1977), 195, 253. Feldmann, R.J., M i l n e G.W.A. Heller, S . R . F e i n Α . Miller, J . Α . , and (1977), 17, 157. The Interagency Regulatory L i a s o n Group (IRLG) was e s t a b 2 August, 1977 by the f o l l o w i n g four Agencies: EPA, FDA, OSHA and CPSC. EPA Order #2800.2, issued 27 May, 1975. Feldmann, R.J., and Heller, S.R., J. Chem. Doc., (1972), 12, 48. CIDS S t r u c t u r e Feature Key Code Manual is a v a i l a b l e from CIS P r o j e c t , Chemistry Department, Brookhaven N a t i o n a l Laboratory, Upton, Long I s l a n d , New York 11973. NIOSH, R e g i s t r y of Toxic E f f e c t s of Chemical Substances (RTECS), 1977. A v a i l a b l e from the US Government P r i n t i n g O f f i c e , GPO Order Number 017-033-0027101; $17.50 per copy USA: $21.88 per copy non-USA. Bracken, Μ., D o r i g a n , J., Hushon, J., and Overbey, II, J., MITRE Reprt MIR-7558 to CEQ, June 1977. Two volumes en titled "Chemical Substances Information Network (CSIN)". NLM Fact Sheet for the T o x i c o l o g y Information Program, January 1978. M i l n e , G . W . A . , Zupan, J., Heller, S . R . , and Miller, J.A., A n a l . Chim. A c t a , In press (1978).

RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

167

11

An

Integrated System for C o n d u c t i n g

Biological

Chemical

and

Searches

T. M . DYOTT, A. M . EDLING, C. R. GARTON, W. O. JOHNSON, P. J. McNULTY, and G. S. ZANDER Rohm and Haas Company, Norristown Road, Spring House,PA19477 Over the past seve t Roh d Haa Compan hav been developing a computerize tion system called ACCI ( A g r i c u l t u r a Computerize Information System)(1). In this paper we will d e s c r i b e the chemical and biological search capabilities which we have built i n t o ACCIS. ACCIS Design

Criteria

ACCIS was developed in order t o : 1.

Accomodate the growing amount of data which r e s u l t e d from expanding biological s c r e e n i n g programs.

2.

Facilitate communication of screening r e s u l t s to r e s e a r c h e r s , a d m i n i s t r a t o r s , and o u t s i d e collaborators.

3.

Reduce the time our biologists spent t r a n s c r i b ing, e x t r a c t i n g , and r e p o r t i n g screening results.

4.

Enhance the value of the s t o r e d screening r e s u l t s by making them readily a v a i l a b l e .

To meet these o b j e c t i v e s we decided that the system must: 1.

c o n t a i n not only the biological screening r e s u l t s , but a l s o the chemical s t r u c t u r e s , reference d a t a , and p e r t i n e n t chemical d a t a , e.g., solubility and purity information.

2.

produce a v a r i e t y of current awareness r e p o r t s on standard 8 1/2 X 11 paper, or 3 X 5 or 5 X 8 c a r d s , and that those r e p o r t s should c o n t a i n h i g h q u a l i t y structural diagrams whenever a p p r o p r i a t e . 0-8412-0465-9/78/47-084-168$05.00 © 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

11.

DYOTT ET

3.

AL.

Chemical

and Biological

Searches

169

provide a convenient mechanism f o r conducting a wide v a r i e t y of chemical and/or b i o l o g i c a l searches.

System O r g a n i z a t i o n ACCIS i s thoroughly i n t e g r a t e d i n t o a everyday o p e r a t i o n of our screening programs. The flow of i n f o r m a t i o n i n t o ACCIS i s diagrammed i n Figure 1. When our chemists synthesize a compound they complete a compound s u b m i t t a l form, g i v i n g the e m p i r i c a l formula, s t r u c t u r a l diagram, chemical name, chemist's name, notebook r e f e r e n c e , department, date, v a r i o u s p h y s i c a l p r o p e r t i e s , screening p r i o r i t i e s , and any s p e c i a l i n s t r u c t i o n s . The chemist then takes the s u b m i t t a l form and the sample i t s e l f to the Screening Information Center. There the i n f o r m a t i o n i s reviewed and entered i n t o the system v i a a chemical t y p e w r i t e r (a modified IBM MCST) sent to the appropriat produced t r a n s m i t t a l sheet which provides the b i o l o g i s t s w i t h the s t r u c t u r a l diagram, u s e f u l p h y s i c a l property i n f o r m a t i o n , and any s p e c i a l i n s t r u c t i o n s . The b i o l o g i s t s then screen the compound, r e c o r d i n g t h e i r f i n d i n g s on 2-part carbonless forms. They keep the f i r s t copy as a l e g a l r e c o r d , w h i l e the second copy i s returned to the i n f o r m a t i o n center where the data are keypunched and read i n t o the system. Whenever data are entered, v a r i o u s current awareness r e p o r t s are a u t o m a t i c a l l y generated which keep the chemists, b i o l o g i s t s , and t h e i r management i n formed and a l l o w them to maintain hardcopy f i l e s . A t y p i c a l ACCIS r e p o r t , the h e r b i c i d e current awareness r e p o r t , i s shown i n Figure 2. (The organism names have been replaced by the l e t t e r s B-L f o r c o n f i d e n t i a l i t y reasons.) AM and AD are average c o n t r o l data f o r a l l monocot and a l l d i c o t s p e c i e s , r e s p e c t i v e ly. The number of screening programs f l u c t u a t e s as new programs are i n i t i a t e d and o l d ones are terminated, but i s g e n e r a l l y i n the range of 8-12. Each screen may i n t u r n i n c l u d e anywhere from 1 to 15 d i f f e r e n t organisms, t r e a t e d under v a r i o u s c o n d i t i o n s and dosages. This v a r i a b i l i t y makes i t e s s e n t i a l that the b i o l o g i s t s i n each area work c l o s e l y w i t h the i n f o r m a t i o n s p e c i a l i s t to design both t h e i r data c o l l e c t i o n forms and the v a r i o u s r e p o r t s they r e q u i r e . Our emphasis i s on meeting the researcher's needs r a t h e r than s i m p l i f y i n g the programming. As a r e s u l t ACCIS: 1.

i s a h i g h l y customized

system.

2.

c o n s i s t s of w e l l over 100 programs, t o t a l i n g approximately 250,000 l i n e s of code.

3.

enjoys extremely

strong user

support.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

170

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OF

MEDICINAL

CHEMICAL

INFORMATION

BIOLOGISTS

BIOLOGY DATA

BOUND PAGE

I

FORM

Figure 1. Flow of information into ACCIS

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

FOR LEGAL

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

1 3

3

1650 N 0S

3

2

2

RATE ( #/A) 8 4 4

RATE ( */A> 8 4 4

7

4

TEST DATE 09/18/74 09/18/74 09/18/74

I O

TYPE TEST PRE PRE PCST

TYPE TEST PRE PRE PCST

TYPE RATE ( */A ) TEST PRE 8 PRE 4 PCST 4

RH 1652 C H CIN 0 S MAYBRIDGE

TEST DATE 09/18/74 09/18/74 09/18/74

s

RH 1651 C|oH F N4 MAYBRIDGE

TEST DATE 09/18/74 09/18/74 09/18/74

MAYBRIDGE

RH C*H

*********•*•*•**•••*•• •COMPANY CONFIDENTIAL* **********************

0

Β 0

D 0

\

F - * - F

F I

/

•—NH—Ν=·—·=Ν

• Ν S Ο · Il II il II J • ·—NH—·—NH—·—·—· \ / I J Κ AM G 0 0 0

ROHM ANO HAAS COMPANY CURRENT AHA«ENESS REPORT HERBICIDE

STA TUS D D 100 D

AD

0

Β 0

0

C

ο ο

ε

Figure 2.

-

ο

0

G

/

A typical ACCIS

AM

\

h

Ο

\

/

J

report format

C

C l

0

Κ 0 0

L 99 -

STA TUS D D D

STA TUS J Κ L F I Ε F AM G C D AD Β 0 40 40 60 7C 0 90 0 90 44 90 100 99 0 30 60 40 30 95 100 32

AD

AREA

03/23/78

172

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CHEMICAL

INFORMATION

The chemical and b i o l o g i c a l i n f o r m a t i o n i n ACCIS i s s t o r e d i n a number of computer f i l e s . The b i o l o g i c a l , m i s c e l laneous chemical, and reference i n f o r m a t i o n i s s t o r e d i n an IMS data base. The s t r u c t u r a l diagram, as entered on the chemical t y p e w r i t e r , and the chemical name are stored i n standard v a r i able record l e n g t h f i l e s . In order to s t o r e the chemical s t r u c tures i n a machine i n t e l l i g i b l e , and t h e r e f o r e searchable, manner we incorporated the Chemical A b s t r a c t s Servic e (CAS) R e g i s t r y I I system i n t o ACCIS. The s t r u c t u r e s are s t o r e d i n a connection t a b l e f i l e and a fragment f i l e i s generated which improves the e f f i c i e n c y of the substructure search system. In a d d i t i o n there are a number of a u x i l i a r y f i l e s which d e s c r i b e the b i o l o g i c a l screens and are used to v a l i d a t e the b i o l o g i c a l data, a l l o w a b b r e v i a t i o n s i n the data base to be expanded i n r e p o r t s (data d i c t i o n a r i e s ) , and supply d i s t r i b u t i o n l i s t s f o r v a r i o u s r e p o r t s . The t o t a s t e a d i l y s i n c e ACCIS m i l l i o n characters. 1

Search C a p a b i l i t i e s We found that i n a d d i t i o n to current awareness r e p o r t s we needed to be able to produce r e p o r t s based on v a r i o u s c r i t e r i a , e.g., s u b s t r u c t u r e , b i o l o g i c a l a c t i v i t y , t e s t date, and/or source. T y p i c a l questions might be: 1.

What 5-halo i s o t h i a z a l o n e s have we made?

2.

What compounds have we screened which c o n t r o l >80% of weed XYZ when a p p l i e d at 2 l b s / a c r e preemergence?

3.

What are the f u n g i c i d e screening r e s u l t s f o r the compounds we obtained from KLM corporation?

4.

What 4 - n i t r o diphenyl-ethers have we made which c o n t r o l >80% of weed RST when a p p l i e d at 4 l b s / a c r e postemergence?

5.

What compounds were screened f o r i n s e c t i c i d a l a c t i v i t y during December 1977?

D i f f e r e n t types of r e p o r t s are a l s o c a l l e d f o r . We might need j u s t the s t r u c t u r e s and reference i n f o r m a t i o n , or s t r u c tures and the screening r e s u l t s from a p a r t i c u l a r area, or s t r u c t u r e s and the screening r e s u l t s from s e v e r a l areas. Since a l l of our common questions are compound o r i e n t e d we designed a modular search system as shown i n Figure 3.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978. Figure 3.

BIOLOGICAL SEARCH PROGRAM

CHEMICAL SEARCH PROGRAM

STRUCTURE AND ALL BIOLOGICAL AREAS REPORT PROGRAM

STRUCTURE AND SPECIFIC BIOLOGICALl AREA REPORT PROGRAMS

Flow diagram of modular ACCIS search system

SELECTED OMPDS.

ρ

STRUCTURE REPORT PROGRAM

RETRIEVAL

174

O F MEDICINAL

CHEMICAL

INFORMATION

A s u i t a b l e chemical search program f o r CAS R e g i s t r y I I f i l e s had already been developed by CAS, w h i l e the v a r i o u s r e p o r t programs are modified v e r s i o n s of current awareness r e p o r t programs we have p r e v i o u s l y developed. The only major new program we needed was one f o r searching the b i o l o g i c a l and r e f e r e n c e i n f o r m a t i o n contained i n the IMS data base. Biological

Search

The b i o l o g i c a l data we need t o search i s contained i n an IMS data base, which has a h i e r a r c h i c a l s t r u c t u r e , as shown i n Figure 4. This h i e r a r c h i c a l s t r u c t u r e allows you t o have any number of t e s t areas w i t h i n a compound, any number of t e s t dates w i t h i n a t e s t area, any number of t e s t types w i t h i n a t e s t date, etc. (There i s of course more d e t a i l e d i n f o r m a t i o n w i t h i n each segment of the data bas We developed a searc search c a p a b i l i t y . I t allows us to q u a l i f y the search or any p i e c e (or pieces) of i n f o r m a t i o n i n the data base and has cons i d e r a b l e Boolean l o g i c c a p a b i l i t i e s . For example, i f we were i n t e r e s t e d i n compounds w i t h i n the range RH-60000 to RH-80000 which were a c t i v e a g a i n s t fungus ABC o r DEF, but d i d not i n j u r e crop XYZ a t a r a t e of 4 l b s / a c r e , we would encode the question as :

(RH>60000*RH<80000) (AREA=F) ( ORGAN I SM=ABC+ORGANI SM=DEF ) (ACTIVITY=A+ACTIVITY=B) (AREA=H) (DOSE=4.00) (0RGANISM=XYZ) (ACTIVITY=0)

Comments * i s a Boolean AND F f o r fungicide -I- i s a Boolean OR f u n g i c i d e a c t i v i t i e s are stored as l e t t e r s H f o r herbicide

h e r b i c i d e a c t i v i t i e s are stored as numbers

The b i o l o g i c a l search system operates i n a batch mode. While i t would be n i c e to have an i n t e r a c t i v e b i o l o g i c a l search system we are confronted w i t h a number of problems, i n c l u d i n g : 1.

our r e p o r t s c o n t a i n s t r u c t u r a l diagrams, r e quiring either a special l i n e printer or a graphics t e r m i n a l .

2.

most of our f i l e s a r e s e q u e n t i a l r a t h e r than random access.

We do not f e e l that i t i s c r i t i c a l f o r our system t o be i n t e r a c t i v e because our batch system turn-around i s u s u a l l y on

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

DYOTT E T A L .

Chemical

and Biological

COMPOUND

RH- 3456

TEST AREA

HERBICIDE

TEST DATE

5/15/78

TEST TYPE

PREEMERGENCE

DOSE INFORMATION

2 LBS/ACRE

TEST ORGANISM

WEED XYZ

EFFECTS NOTED

85% CONTROL

Figure 4.

Searches

MISC. CHEM. & REFERENCE INFORMATIO

Hierarchical structure of biology data hase

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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CHEMICAL

INFORMATION

the order of 30-60 minutes. We a r e , however, planning to develop a c o n v e r s a t i o n a l i n t e r a c t i v e front-end program which w i l l a l l o w us to conveniently enter a search from a keyboard t e r m i n a l i n our own l a b o r a t o r y and w i l l a u t o m a t i c a l l y i n i t i a t e the batch search program. Substructure Search Our s u b s t r u c t u r e search system i s based on the CAS Subs t r u c t u r e Search System(2) which we implemented i n 1975. This system i s reasonably e f f i c i e n t i n terms of computer time, making use of a fragment screen, f o l l o w e d by an atom-by-atom i t e r a t i v e search of the compounds which pass the fragment screen. The schematic i n F i g u r e 5 shows the o v e r a l l flow of the system. The CAS Substructure Search System provides a h i g h degree of f l e x i b i l i t y , with severa l o g i c . Encoding searche problems : 1.

r e q u i r e d coding the query t w i c e , once as f r a g ments, once as a s u b s t r u c t u r e connection t a b l e .

2.

r e q u i r e d that the user be f a m i l i a r w i t h the d e t a i l s and i d i o s y n c h r a s i e s of the system, e.g., fragment screens and encoding t e c h niques.

These d i f f i c u l t i e s r e s u l t e d i n e r r o r s , i n c r e a s e d the time r e q u i r e d to conduct a search, and, t h e r e f o r e discouraged our s c i e n t i s t s from making f u l l use of the system. In order to e l i m i n a t e these problems, i n 1977 we converted the system from a c a r d - o r i e n t e d batch system to an i n t e r a c t i v e computer graphics system. Since we had no d e s i r e to t r y to a l t e r the CAS system i t s e l f , we designed and developed i n t e r a c t i v e computer graphics pre- and p o s t - p r o c e s s o r s . The preprocessor allows the user to simply draw i n the d e s i r e d subs t r u c t u r e w h i l e r e t a i n i n g a l l of the f l e x i b i l i t y of the CAS system. I t was engineered so that s c i e n t i s t s can e a s i l y conduct t h e i r own searches, although most (-80%) s t i l l p r e f e r to have the chemical i n f o r m a t i o n s p e c i a l i s t do i t . The postprocessor allows the user to view as many of the h i t s as des i r e d and to s p e c i f y which s t r u c t u r a l and/or b i o l o g i c a l r e p o r t s should be prepared. The s p e c i f i e d r e p o r t s are then p r i n t e d by a background batch job ( a u t o m a t i c a l l y i n i t i a t e d by the p o s t processor) and are u s u a l l y a v a i l a b l e w i t h i n 30-60 minutes. The flow of t h i s system i s depicted i n F i g u r e 6. Using the system i s very s t r a i g h t forward. I f we want to search f o r

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

\

I I

QUERY

FRAGMENT

QUERY

ITERATIVE

^1

FRAGMENT

Τ

SEARCH

/

FILE

IMAGE

FILE

STRUC.

CONN. TABLE

SEARCH

/

B Y ATOM

ITERATIVE

ATOM

Flow diagram of CAS substructure search system

SSS SYSTEM

Figure 5.

CAS

HITS

FRAG.

BASE

DATA

BIOLOGY

178

RETRIEVAL

Figure 6.

O F MEDICINAL

CHEMICAL

INFORMATION

Flow diagram of interactive substructure search system

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

11.

DYOTT E T A L .

Chemical

and

Biological

Searches

179

0 or S

II

R

2

i =-

R

2

c = c

o r

=-NH , -NH-C, or - N ^ 2

we merely draw the f o l l o w i n g on the graphics t e r m i n a l , v i a a j o y s t i c k , c u r s o r , l i g h t buttons.

0,S

Al—C=C

A2—Ngl

A2—

A2—

M2

y

A l t o A10 stand f o r a l t e r n a t i v e s . (§1 means the atom can only have 1 non-hydrogen attachment, @2 two non-hydrogen a t t a c h ments, e t c . With t h i s system a t y p i c a l search can be completed i n 10-20 minutes, which can be broken down as f o l l o w s : 1. e s t a b l i s h i n g computer l i n k 2. enter s u b s t r u c t u r e 3. search 4. view s t r u c t u r e s h i t 5. s p e c i f y d e s i r e d r e p o r t s 6. terminate computer l i n k

1 minute 2-4 3-5 3-10 .25 .25 10-20 minutes

Our s c i e n t i s t s are very e n t h u s i a s t i c about the new i n t e r a c t i v e graphics s u b s t r u c t u r e search system. The number o f subs t r u c t u r e searches conducted increased s i g n i f i c a n t l y a f t e r i t s i n t r o d u c t i o n , and continues t o i n c r e a s e . We c u r r e n t l y process an average of two s u b s t r u c t u r e search requests a week. Other Uses We can conduct combination chemical and b i o l o g i c a l searches

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

180

w i t h our e x i s t i n g search systems. The substructure search s y s tem produces a f i l e of the RH numbers of the compounds which met the search c r i t e r i a . This l i s t i s then used to r e s t r i c t the range of the b i o l o g i c a l search. We have a l s o developed search and r e t r i e v a l programs which a l l o w us to e x t r a c t connection t a b l e s and b i o l o g i c a l data for use i n v a r i o u s data a n a l y s i s systems. Summary We have developed v e r s a t i l e and convenient systems f o r searching the vast amounts of chemical and b i o l o g i c a l data generated by our screening programs; s i g n i f i c a n t l y i n c r e a s i n g the value of the i n f o r m a t i o n obtained by g r e a t l y f a c i l i t a t i n g access to i t . Acknowledgements We wish to thank the Chemical A b s t r a c t s S e r v i c e f o r p r o v i d i n g us w i t h programs and documentation for t h e i r R e g i s t r y I I and Substructure Search systems. We appreciate the s p e c i a l a t t e n t i o n Mr. Charles R o l l e and Dr. Dale Myers gave to us. We a l s o appreciate the guidance offered by M r . Harold Bewicke, Mr. Richard Dudeck, Mr. Robert B . Smith, Mr. Dugald Brooks and D r . John Tinker of Eastman Kodak Company on the use of the R e g i s t r y I I system. F i n a l l y , we would l i k e to acknowledge the e f f o r t s of a l a r g e number of people throughout Rohm and Haas who helped ACCIS become a r e a l i t y : D r . H.O. Bayer, Mr. Marvin B e l l , Mr. Howard R. Boehringer, M r s . Sandra L . B u c k l e y , Mr. Stephen G. Cohen, D r . Joseph T. G i l b e r t , Mrs. Nancy A . Kippenhan, D r . George A. M i l l e r , M r . Thomas N . Manuel, M r . Thomas W. Raezer, Mr. Vernon L . R i c h e n s , Mrs. E i l e e n B. Rothrock, D r . Alden S p e l l , Mrs. Marie M. S t e i n i t z , and D r . Warren H . Watanabe. Literature Cited 1.

Buckley, S.L., Cohen, S.G., D y o t t , T.M., Garton, C . R . , Gilbert, J.T., Kippenhan, N.A., McNulty, P.J., and Raezer, T.W., paper presented at the 173rd N a t i o n a l Meeting of the ACS at New Orleans, March 1977.

2.

Spann, M . L . and

Willis,

D . D . , J. Chem. D o c . , 11, 43 (1971)

RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

12

An

Integrated C h e m i c a l a n d B i o l o g i c a l D a t a R e t r i e v a l

System for

Drug

Development

1

J. A. PAGE , R. THIESEN, and F. KUHL Walter Reed Army Institute of Research, Bethesda, MD 20014

The Division of Experimenta Army Institute of Research Biometrics has been engaged in the development and implementation of a large scale integrated chemical - biological data retrieval system for the support of the Army Medical Research and Development Command's drug development a c t i v i t i e s . The system i s being developed on a Control Data Corporation 3500 with one million bytes of memory, 16 disk drives with removable packs which contain 37 million bytes of storage each, six 7-track tape drives, two line printers, and 16 communication lines supporting line speeds of 110, 300, and 1200 baud. This effort represents a total redesign of the original system which was described earlier [1].

F i l e Organization The WRAIR Chemical Information Retrieval System (CIRS) is comprised of four subsystems: Biology, Inventory, Chemistry and the Report Generator. The f i r s t three subsystems contain f i l e s of information peculiar to each system, and programs for searching these f i l e s . The Report Generator is used to combine and sort output from searches of the other subsystems. The subsystems must be searched separately because they are too large to be searched together. The output from any subsystem may be used to control the search of the next, by means of a common key. For example, a chemistry search yields a number of structures, each of which is identified by a unique accession number. These numbers might then be used to garner information from Biology and Inventory relative to samples of the structures whose numbers come from Chemistry. Or, the l i s t of sample numbers from an Inventory search might be used to extract information from Chemistry 1

Present address: Uniformed Services University of the Health Sciences, Bethesda, MD 20014. This chapter not subject to U.S. copyright. Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

182

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O F MEDICINAL

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r e l a t i n g t o those samples. In both examples, the Report Genera t o r would combine the information from the various subsystems and s o r t the r e p o r t i n t o the d e s i r e d order. The standard CIRS r e p o r t may contain information from any o f the subsystems alone, o r from any two, or from a l l three. Chemistry R e t r i e v a l Subsystem. The chemistry r e t r i e v a l subsystem f i l e design and o r g a n i z a t i o n i s being d e s c r i b e d i n d e t a i l f o r p u b l i c a t i o n elsewhere [2]. B r i e f l y the system cons i s t s o f two numeric index cross reference f i l e s , a screen index f i l e , and a master s t r u c t u r e f i l e . I t contains about 270,000 unique s t r u c t u r e s and occupies 8 d i s k packs of 37 m i l l i o n chara c t e r s each. The three index f i l e s provide a cross indexing scheme that allows f o r f l e x i b i l i t y i n sequencing and updating. The system may be accessed by 1) a c c e s s i o i n concept t o the CAS r e g i s t r chemistry update system t o each new s t r u c t u r a l formula, 2) sample number, which i s a unique, s e q u e n t i a l number assigned to each p h y s i c a l sample without regard t o the chemical s t r u c t u r e by the inventory update system, o r 3) chemical s t r u c t u r e s , e i t h e r whole or sub-structures. The a c c e s s i o n index f i l e contains the accession number f o r a given s t r u c t u r a l formula and a t a b l e of sample index records f o r each a c c e s s i o n number. T h i s sequence provides quick access t o data f o r a l l samples o f a p a r t i c u l a r chemical. In order t o provide c o n t i n u i t y and allow f o r the expression of a h i e r a r c h i c a l r e l a t i o n s h i p the a c c e s s i o n number i s s t r u c t u r e d so t h a t f u n c t i o n a l l y d i f f e r e n t f i l e s may be maintained and s a l t s may be t i e d , through t h e i r a c c e s s i o n number, to the parent compound. The p a r t s and f u n c t i o n s o f the p a r t s are as f o l l o w s : 1) A two d i g i t alpha p r e f i x designates s e r i e s . C u r r e n t l y only two s e r i e s are being used: "WR" f o r s t r u c t u r e s f o r which a p h y s i c a l sample has been r e c e i v e d f o r screening and "XR" f o r s t r u c t u r e s proposed or under c o n s i d e r a t i o n but not a c t u a l l y r e c e i v e d . An a d d i t i o n a l s e r i e s f o r r e l a t e d s t r u c t u r e s reported i n the l i t e r a t u r e i s planned. The s e r i e s p r e f i x i s a u t o m a t i c a l l y up-graded t o "WR" i f the compound i s r e c e i v e d and processed through the inventory system. 2) A s i x d i g i t s e q u e n t i a l number which i d e n t i f i e s the p r i mary chemical s t r u c t u r e . 3) A two d i g i t numeric " s a l t s u f f i x " which i s assigned by the update system t o d i f f e r e n t s a l t s of compounds having the same primary s t r u c t u r e . T h i s allows the user t o r e t r i e v e a s p e c i f i c compound and a l l of i t s s a l t forms without doing a sub-structure search. I t a l s o allows data on a given compound and a l l o f i t s s a l t forms t o be grouped together on an a c c e s s i o n number sequenced r e p o r t .

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The sample index f i l e i s keyed by the sample or b o t t l e number. T h i s number i s c r o s s - r e f e r e n c e d t o the accession number so t h a t a given sample may be attached t o a s p e c i f i c s t r u c t u r e . The sequence permits the chemistry subsystem d i r e c t access t o e i t h e r the b i o l o g y o r the inventory subsystem and provides f o r d i r e c t access o f the s t r u c t u r e s f o r r e p o r t s by the inventory and/or b i o logy subsystems. The sample index f i l e a l s o contains some admini s t r a t i v e i n f o r m a t i o n about each sample such as the source; the method by which the sample was obtained (e.g. g i f t , purchased, e t c . ) , whether t h i s sample i s the o r i g i n a l submission o r a dup l i c a t e , d i s c r e e t ( i . e . , p r o p r i e t a r y ) o r open. The screen index f i l e i s the f i r s t f i l e accessed f o r any s t r u c t u r e o r sub-structure search. I t contains a l l the informat i o n necessary t o determine s t r u c t u r e matches. When the s t r u c t u r e matches have been l o c a t e d , a d d i t i o n a l information f o r each s t r u c t u r e , such as th the a c c e s s i o n number. Becaus t i a l , the screen index f i l e may be accessed e i t h e r s e q u e n t i a l l y , or s e l e c t i v e l y by use o f the i t s indexes. Each s t r u c t u r e has i t s own record on the screen index. The c h i e f items s t o r e d f o r each are the connection t a b l e ( i n a compressed, non-redundant format), and the s t r u c t u r e ' s unique acc e s s i o n number. The key f o r each r e c o r d c o n s i s t s o f the acc e s s i o n number, preceded by the s t r u c t u r e screen and the p a r t i t i o n i n g f a c t o r . The screen i s a 96-bit superimposed code d e r i v e d a l g o r i t h m i c a l l y from the s t r u c t u r e . I t has been described i n d e t a i l by Feldman [3]. I f two s t r u c t u r e s have d i f f e r e n t screens, they must have d i f f e r e n t s t r u c t u r e s . Thus only those f i l e s t r u c t u r e s having the same screen as a given query compound are cand i d a t e s f o r matching. I t e r a t i v e matching w i l l be necessary t o confirm the matches, but the amount o f i t e r a t i v e matching r e q u i r e d i s d r a s t i c a l l y reduced by the screen. For sub-structure searches, the i n c l u s i v e property o f the screen becomes s i g n i f i c a n t . In the example below, the f i r s t s t r u c t u r e (discounting hydrogens which are not considered i n the c a l c u l a t i o n o f the screen) i s wholly contained by the second and as a sub-structure would be a m a t c h —

The screen f o r the f i r s t s t r u c t u r e i s a l s o wholly contained i n the screen f o r the second, i . e . f o r each b i t s e t i n the f i r s t screen, the corresponding b i t i s set i n the second. To match a sub-structure then, a candidate's screen must have a t l e a s t a l l the b i t s t h a t a r e set i n the query's screen. The e f f e c t i v e n e s s of t h i s system i n e l i m i n a t i n g f i l e compounds from c o n s i d e r a t i o n depends on the nature o f the sub-structure and v a r i e s g r e a t l y .

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The p a r t i t i o n i n g f a c t o r i s conceptually s i m i l a r to Hode's bucket index [ 4 ] . I t i s a 12 b i t code d e r i v e d from the screen through a s e r i e s o f AND and OR operations i n such a way that the i n c l u s i o n p r o p e r t i e s o f the screen are preserved. Its function i n the screen index f i l e i s to a l l o t records to one of 4096 p a r t i t i o n s with a t h e o r e t i c a l l y uniform d i s t r i b u t a t i o n . Therefore, i n a f i l e o f 250,000 records the expected number of records i n a given p a r t i t i o n i s 61. Since f o r i d e n t i t y searches, the f a c t o r and screen o f the query must be matched e x a c t l y only t h i s very small p o r t i o n o f the f i l e need be read p r i o r to the search. The u t i l i z a t i o n of the p a r t i t i o n i n g f a c t o r i n the subs t r u c t u r e search i s more complex. Any compound c o n t a i n i n g a given sub-structure w i l l have a p a r t i t i o n i n g f a c t o r which cont a i n s a t l e a s t those b i t s set i n the sub-structure's p a r t i t i o n i n g f a c t o r . As s u b - s t r u c t u r e queries become more s p e c i f i c more screen b i t s are u s u a l l t i t i o n i n g f a c t o r . The numbe the f a c t o r drops e x p o n e n t i a l l y as the number of one b i t r i s e s . Because the screen index has the p a r t i t i o n i n g f a c t o r as i t s major key, i t i s necessary to read only those records having the r i g h t factor. I f , however, the sub-structure i s so general that more than one t h i r d o f the p a r t i t i o n s must be accessed randomly i t i s quicker t o scan the screen index f i l e s e q u e n t i a l l y . The master f i l e contains the chemical s t r u c t u r e , which has been captured a t i n p u t and saved i n a condensed form. I t i s sequenced by a c c e s s i o n number as t h i s number i s a u t o m a t i c a l l y assigned to a new s t r u c t u r e by the f i l e update system. In add i t i o n to the s t r u c t u r e , the molecular formula and q u a l i f i e r s are in this f i l e . The molecular formula has been stored i n such a way as to permit searching both as an exact match or an i n c l u s i v e match. T h i s format a l s o permits the s o r t i n g of matches by molec u l a r formula i n t o CAS sequence f o r r e p o r t i n g . Because the connection t a b l e s are e s s e n t i a l l y two-dimensiona l , and do not c o n t a i n s p e c i a l bond types, many chemical propert i e s such as stereochemistry cannot be represented. The s o l u t i o n t o t h i s and s i m i l a r problems was the i n c l u s i o n of machinereadable q u a l i f i e r f i e l d s f o r each s t r u c t u r e to i n d i c a t e such t h i n g s as stereo i n f o r m a t i o n , polymers, mixtures, and c o o r d i n a t i o n complexes. Each q u a l i f i e r has a l s o non-searchable f r e e t e x t s t o r e d with i t to a i d human i n t e r p r e t a t i o n of the p i c t u r e . B i o l o g y R e t r i e v a l Subsystem. The b i o l o g y r e t r i e v a l subsystem c o n s i s t s o f two indexed s e q u e n t i a l f i l e s c o n t a i n i n g b i o l o g i c a l t e s t data r e l a t i n g to the s t r u c t u r e s of the chemistry subsystem. There are over three m i l l i o n records occupying 6 d i s k packs of 37 m i l l i o n c h a r a c t e r s each. Both f i l e s are sequenced by sample number (BN) and l a b o r a t o r y i d e n t i f i c a t i o n number (Lab I.D.). The data f i e l d s are dependent on the type of e x p e r i mentation done by a s p e c i f i e d l a b o r a t o r y and are predefined i n a data name d i c t i o n a r y . From a u s e r s p o i n t of view the two f i l e s 1

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are i d e n t i c a l . The d i v i s i o n i s a r b i t r a r y and i s designed to allow searching only p a r t o f the data base. The primary f i l e contains those l a b ID's most f r e q u e n t l y accessed while the other f i l e contains a number o f secondary t e s t systems and h i s t o r i c a l data. New l a b o r a t o r i e s can be added t o the system by simply adding e n t r i e s i n t o the data name d i c t i o n a r y under a new l a b ID number. Inventory R e t r i e v a l Subsystem. The inventory r e t r i e v a l subsystem i s an indexed s e q u e n t i a l f i l e c o n t a i n i n g information p e r t i n e n t t o the p h y s i c a l samples. I t c u r r e n t l y contains 433 thousand records and occupies 5 d i s k packs of 37 m i l l i o n chara c t e r s each. The f i l e i s maintained i n sample number sequence. When a sample i s r e c e i v e d i t i s assigned the next a v a i l a b l e sample number and a l l a v a i l a b l e data ( i . e . , date o f r e c e i p t , source, amount, c o n d i t i o n o f r e c e i p t , s h e l f l o c a t i o n , chemical and p h y s i c a l p r o p e r t i e s transactions involving o r a t o r i e s , removal from inventory, etc.) and the date of the t r a n s a c t i o n s a r e a l s o entered i n t o record. The data f i e l d s f o r t h i s f i l e a r e a l s o p r e d e f i n e d i n a data name d i c t i o n a r y f o r searching. Retrieval C r i t e r i a Chemical Subsystem. The heart o f the chemical r e t r i e v a l subsystem i s the sub-structure search c a p a b i l i t y . The general purpose o f sub-structure searching i s to r e t r i e v e compounds having s p e c i f i e d s t r u c t u r a l s i m i l a r i t i e s . In our system, the s i m i l a r i t i e s a r e s p e c i f i e d i n the form o f an incomplete s t r u c ture, which must be i n c l u d e d i n any f i l e s t r u c t u r e that i s t o be r e t r i e v e d . While the f i l e s t r u c t u r e may contain atoms and i n terconnections not shown i n the query, those i n the query must be matched. Thus, a query sub-structure may contain normal s t r u c t u r e atoms and bonds, and i n d e f i n i t e atoms o r bonds. The former must be matched e x a c t l y , and the l a t t e r may be s u b s t i t u t e d according to the r u l e s governing the p a r t i c u l a r atom or bond. S t r u c t u r e s , e i t h e r queries or f i l e compounds, are represented by a connection t a b l e . The t a b l e contains an entry f o r each non-hydrogen atom, together with information on the numbers and s i z e s o f covalent bonds on each atom, and the other non-hydrogen atoms attached t o i t ( c a l l e d "neighbors"). Each entry a l s o shows the number o f hydrogens attached t o the atom, any i o n i c charges, and a f l a g t h a t i s set i f the atom i s i n a r i n g . We have d e l i b e r a t e l y discarded the knowledge o f what type o f bond attaches which neighbor, not because i t i s u n i n t e r e s t i n g but because i t allows resonating s t r u c t u r e s , such as phenyl r i n g s , t o appear i d e n t i c a l r e g a r d l e s s o f the p r e c i s e arrangement o f double and s i n g l e bonds. We a l s o make c e r t a i n adjustments to tautomers to allow them t o be i d e n t i f i e d by e i t h e r form r e g a r d l e s s o f which

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form i s used f o r input. The d e t a i l s o f t h i s have been discussed elsewhere [ 5 ] . Our connection t a b l e s are not capable of d i s t i n g u i s h i n g stereoisomers or polymers. But codes f o r the presence of such c o n d i t i o n s and t e x t e x p l a i n i n g them are stored with the o r i g i n a l i n p u t formula and are r e t r i e v e d with i t . These are the q u a l i f i e r s mentioned above. They may a l s o be s p e c i f i e d f o r a chemis t r y search. Normal s t r u c t u r e s are coded f o r input by means of a s p e c i a l l y - m o d i f i e d t e l e t y p e [£J, which allows the s t r u c t u r a l formula to be typed as a combination o f atoms and bonds to represent chains and r i n g s . I t a l s o allows s t r i n g s of s u b s c r i p t e d element symbols and groups i n c l o s e d w i t h i n parentheses, whose connections must be i n f e r r e d . The extensive l o g i c necessary to i n t e r p r e t these formu l a s has been described [ 7 ] . The r e s u l t i s a f a i r l y simple s e t o f r u l e s f o r the chemist w r i t i n l y corresponds to norma are complete, and except f o r c e r t a i n Markush-type s t r u c t u r e s , no ambiguity or s u b s t i t u t i o n i s allowed a t any p o i n t . Queries, on the other hand, are incomplete s t r u c t u r e s , allowing a d d i t i o n s and substitutions at specified points. Most query atoms are normal atoms. That i s , they are not s p e c i a l atoms, they have no u n s p e c i f i e d bonds and t h e i r valance i s not zero. I t i s r e q u i r e d t h a t they match f i l e atoms. The f i l e s t r u c t u r e must c o n t a i n one i d e n t i c a l atom f o r each normal atom i n the query. I f the query atom i s i n a r i n g a f l a g i s s e t i n the atom d e s c r i p t o r word and the f i l e atom must a l s o be i n a r i n g . However, i f the query atom i s not i n a r i n g , the f i l e atom need not be i n a r i n g , but i t i s allowed to be. For example:

Ζ - ΝΗ - Ζ

w i l l allow

If you wish t o f o r c e a query atom to be matched only by a f i l e atom which i s a r i n g member, the query atom must be i n a r i n g . I f the query cannot be w r i t t e n i n such a way as to include the p a r t i c u l a r query atom i n a r i n g , r i n g members may perhaps be s p e c i f i e d with a s p e c i a l atom. The simplest type o f s u b s t i t u t i o n i s that o f a s p e c i a l atom. They appear i n the query as atoms with s p e c i a l symbols and may be r e p l a c e d i n the f i l e s t r u t u r e by any atom meeting the c r i t e r i a they impose. In F i g u r e 1, the query s t r u c t u r e contains two spec i a l atoms, an "X" which allows the s u b s t i t u t i o n of any non-hydro gen atom and a Q" which allows the s u b s t i t u t i o n o f any nonhydrogen, non-carbon atom. These s p e c i a l atoms may appear any where w i t h i n the query s t r u c t u r e , that i s , they need not be t e r minal atoms but may be incorporated i n a s t r i n g or i n a r i n g . In order t o be a " h i t " t o a query a f i l e atom need only have a t l e a s t the bonds, charges e t c . , i n d i c a t e d f o r a s p e c i a l atom. 11

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Therefore, the f i l e compounds i n F i g u r e 1 contain many atoms other than the normal atoms and the s p e c i a l atoms i n the query. The s p e c i a l atoms allowed and t h e i r r e s t r i c t i o n on r i n g membership are given i n Table 1.

Symbol Ζ X Xr Xc Q Qr Qc Ha Mt Rc Cc

Table I. Types of S p e c i a l Atoms Atom Type Any Not Η Not Η Not Η Not H, not C Not H, not C Not H, not C

Carbon Carbon

Ring Membership Indifferent Indifferent Required Excluded Indifferent Required Excluded

Required Excluded

Any atom i n the query, i n c l u d i n g s p e c i a l atoms may c a r r y a charge, which must then be matched by the f i l e atom. The i n v e r s e however, i s not t r u e . That i s , the absence of a charge on a query atom does not preclude a charged f i l e atom as a match. Because the valence of s p e c i a l atoms i s indeterminate (except f o r Ha, Rc, Cc), a l l s p e c i f i c a l l y r e q u i r e d bonds to a s p e c i a l atom must be shown e x p l i c i t l y . The r i n g and chain carbons (Rc and Cc) may be used to allow one to w r i t e p a r t of a r i n g as a chain, o r to exclude r i n g s , e s p e c i a l l y fused r i n g s , as answers. (See F i g u r e 2). F i g u r e s 3,4, and 5 show the r e l a t i o n s h i p s among the s p e c i a l atoms and how they may be used to modify a query so that i t becomes more general or more s p e c i f i c depending on the nature and the number of matches d e s i r e d . Figure 3 d i v i d e s the universe of p o s s i b l e s u b s t i t u t i o n s i n t o e i g h t c a t e g o r i e s and l i s t s which of these c a t e g o r i e s w i l l be r e t r i e v e d by each s p e c i a l atom. Figure 4 shows r e p r e s e n t a t i v e s t r u c t u r e s f o r each category s i n g l y sub s t i t u t e d on a methyl group and which of these s t r u c t u r e s would be r e t r i e v e d by each s p e c i a l atom. F i g u r e 5 shows a few of the p o s s i b i l i t i e s f o r an ortho d i - s u b s t i t u t e d phenyl r i n g . These simple examples g i v e , of course, only an i n d i c a t i o n of the v e r s i t i l i t y p o s s i b l e . Combinations of these few s p e c i a l atoms pro v i d e s a very powerful sub-structure search c a p a c i t y . The other major query element i s the u n s p e c i f i e d bond, w r i t ten as any bond overstruck with a question mark. In general, the u n s p e c i f i e d bond may be used to allow the connections on the connected atoms to vary, as long as the neighbor r e l a t i o n i s maintained. Used between two normal atoms, i t r e q u i r e s the two

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Query:

Matches:

Figure 1.

Example of a simple substructure query

Query A: C R R -C C

C

C

C

Matches:

Q

Ci* (Τ' NH

2

Ouery B:

ζ

Matches:

CH

3

Figure 2.

CH CH3 2

Substructure query using R and C c

c

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Ha

H

1

2

C

Data Retrieval

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S

C ring

7

6

System

8

Ζ

= 18

Qr =

6-7

X

= 28

Ha =

2

Xc = 2-5 Xr

= 68

Q

= 2,3,4,6,7

allowed by the special atoms

Qc = 2 4

CH — 3

Query —

Ζ

Xc

•

•

•

•

•

•

•

•

•

•

CH3*Cd-CH3

•

•

•

•

•

CH -NH

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

CH

Xr

Qr

X

Response 1

Q

Qc

Ha

Mt

Cc

Rc

•

4

CH3CH3

CH3-C1

3

2

CH -S^~[ 3

Figure 4.

• •

• • •

•

Substructure substitution at a single point

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atoms t o be neighbors, but allows the valence o f the two atoms t o vary (Figure 6) o r the nature o f the attachment between the atoms t o vary (Figure 7). A s i n g l e query may c o n s i s t o f a sub-structure fragment with normal atoms and any number and combination o f s p e c i a l atoms and u n s p e c i f i e d bonds. I t may i n f a c t c o n s i s t o f only s p e c i a l atoms. I t may a l s o c o n s i s t o f s e v e r a l sub-structure fragments each o f which may have s p e c i a l atoms and u n s p e c i f i e d bonds. These f r a g ments may be r e l a t e d t o each other i n any combination o f three ways. I f the fragments are simply disconnected, each fragment must be d i s t i n c t l y and simultaneously present i n the f i l e s t r u c t u r e . I f however two fragments are r e l a t e d through the Boolean operator "AND", they are matched independently. Thus i f p a r t s o f the fragments are i d e n t i c a l , those i d e n t i c a l p a r t s are redundant and need not be d i s t i n c t l y present. For example:

X -^~"^-X · X-CH r e q u i r e s a t l e a s t two CI atoms i n the response.

C1-^"""^CHC1 N0 -^^-CH CHCH CI 2

2

2

while

2

CI

X-^ "Vx AND X-CH -CI AND CI 2

allows two CI atoms i n the response

H 0 -^~~^-CH Cl

but only r e q u i r e s one.

CI CH CH -^^-NHCH CH

2

2

2

2

r

CICH CH "-^ ^-CCI 2

2

etc.

i n a d d i t i o n t o the f i r s t responses. Two fragments may a l s o be r e l a t e d through the Boolean ope r a t o r "AND NOT". In t h i s case the f i l e s t r u c t u r e must not match the s p e c i f i e d fragment. Each query may c o n t a i n up t o 32 such fragments i n any combination t h a t i s not d i r e c t l y c o n t r a d i c t o r y . B i o l o g y and Inventory R e t r i e v a l Subsystems. E s s e n t i a l l y the same programs a r e used t o search the b i o l o g y and inventory systems. The major d i f f e r e n c e i s i n the data name d i c t i o n a r y that i s attached. Each subsystem has a d i c t i o n a r y o f a l l data items in i t s f i l e . T h i s provides the c a p a b i l i t y o f searching on any f i e l d o r combination o f f i e l d s i n e i t h e r data base. A f i e l d may be d e f i n e d as numeric, alpha, alphanumeric o r as a repeating group. A l s o a d d i t i o n a l f l e x i b i l i t y i s provided by a l l o w i n g new f i e l d s t h a t are not i n the data name d i c t i o n a r y to be d e f i n e d and used i n the search. The search i s made up o f a search command (SUBSET, o r SUBSET, USING), the f i e l d ( s ) t o be s e l e c t e d as d e f i n e d

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Query: SfC-C

Matches: CH SCH CH 3

2

Ο <

3

0 CH3-S-CH3

O CH3S-CCH3

S-0

S CH3COH

0 Figure 6.

Unspecified bond query

Query: NfN

Matches: N=N

CH Crf-NNHCH 3

Figure 7.

2

Ο

Unspecified bond query

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i n the d i c t i o n a r y , and the search c r i t e r i a . The r e t r i e v a l system i s capable o f handling up to ten imbedded ANDed or ORed f u n c t i o n s as search c r i t e r i a . There are f i v e operations which are used with the data f i e l d s to make up the search c r i t e r i a . They are EQUAL, GREATER THAN, LESS THAN, CONTAINS (which compares f o r a s p e c i f i c s t r i n g o f characters) and the NOT of each. The CONTAINS operator used with the word KEY works as a p a r t i t i o n search using only the major p a r t of the key. Thus i t f u n c t i o n s as a generic search. Searches using repeating groups must use a s u b s c r i p t i n the data items d e c l a r e d as r e p e a t i n g i n the d i c t i o n a r y . For a s p e c i f i c occurance of a r e p e a t i n g group, a number s u b s c r i p t i s used i n the search c r i t e r i a . The s u b s c r i p t ALL i s used when a l l occurrences must meet the search c r i t e r i a . Searching

Procedures

Chemistry Subsystem i n e i t h e r an o n - l i n e or batch mode. Each mode has d i f f e r i n g c a p a b i l i t i e s and uses. The o n - l i n e system w i l l perform 4 d i s t i n c t types of searches: 1) by a c c e s s i o n number; 2) by sample number; 3) by f u l l s t r u c t u r e , or i d e n t i t y search; 4) simple sub-structure search. A l l o n - l i n e f u n c t i o n s use an IMLAC PDS-4 i n t e l l i g e n t graphics t e r m i n a l . The IMLAC machine contains a small computer with 8K of memory, and a d i s p l a y processor d r i v i n g a graphics CRT. Struct u r e s are represented i n the IMLAC by the character set developed f o r the chemical t e l e t y p e [£]. T h i s character set allows twodimensional r e p r e s e n t a t i o n of most s t r u c t u r e s . Each c h a r a c t e r , along with the blank, the backspace, the l i n e feed and the r e verse l i n e feed, has i t s own 7-bit ASCII code, and a p i c t u r e i s s t o r e d i n the IMLAC as a s e r i e s of such codes. The IMLAC processor i s programmed to i n t e r p r e t the codes and draw the c o r r e sponding c h a r a c t e r s on the CRT. The IMLAC i s a l s o programmed to allow i t s operator to enter or e d i t such p i c t u r e s with i t s keyboard. P i c t u r e s may a l s o be sent or r e c e i v e d to or from the host computer. Thus, answers may be d i s p l a y e d to the IMLAC operator by t r a n s m i t t i n g the ASCII r e p r e s e n t a t i o n of the s t r u c t u r e v i a phone l i n e to the IMLAC. The IMLAC could i n f a c t be used f o r primary input r a t h e r than the t e l e t y p e and i n a system with l e s s thruput t h i s would be d e s i r a b l e . The t e l e t y p e s are used because they are much l e s s expens i v e , we already owned them, and the operators are f a m i l i a r with then. The f i r s t three types of o n - l i n e r e t r i e v a l s l i s t e d above were designed to r e p l a c e manually-searched card f i l e s . With the program, the operator may r e t r i e v e and d i s p l a y s t r u c t u r e s by knowing e i t h e r the a c c e s s i o n number, the sample number, or the structure i t s e l f . In the case of an i d e n t i t y s t r u c t u r e search,

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the i n d e x - s e q u e n t i a l design of our connection-table f i l e allows the s t r u c t u r e to be r e t r i e v e d i n l e s s than 5 seconds, and the p i c t u r e to be d i s p l a c e d i n another 5 seconds. Since the s t r u c ture screen i s computed from the s t r u c t u r e i t s e l f , only the s t r u c t u r e must be entered f o r i d e n t i t y q u e r i e s . The person e n t e r i n g the query need not know the index c r i t e r i a . The o n - l i n e sub-structure search was intended o r i g i n a l l y as a t o o l f o r t e s t i n g the system, but has been made a v a i l a b l e to s e l e c t e d users o f the system. Only the simplest searches are allowed: There i s no B o l l e a n combination, nor i s there any a b i l i t y t o search any information except the s t r u c t u r e s . (This means, among other t h i n g s , t h a t the e n t i r e data base i s e l i g i b l e f o r the r e p o r t , r e g a r d l e s s of the p r i v a c y a t t a c h i n g to any compound. Since d i s c r e e t compounds are thus a v a i l a b l e , access to the program must be r e s t r i c t e d . ) The f u l l range of s p e c i a l atoms, u n s p e c i f i e d bonds, and o n - l i n e user. Answers number only (not by sample number), each s t r u c t u r e being d i s p l a y ed as the user asks f o r i t . I f the corresponding sample numbers are d e s i r e d they can be obtained by requesting a l l sample numbers for the given a c c e s s i o n number. The usefulness to the WRAIR S t a f f of searching f o r subs t r u c t u r e s o n - l i n e has yet to be determined. Since the chemistry r e t r i e v a l system uses the screen and connection t a b l e generated by the query to search to screen index f i l e f o r e i t h e r a whole or a sub-structure no more information ( d i s k - d r i v e s ) i s needed o n - l i n e f o r sub-structure searching than f o r i d e n t i t y matches, so one i s no more c o s t l y than the other, i n terms of d i s k resources. But the elapsed time needed f o r such sub-structure searches v a r i e s g r e a t l y and may be l a r g e . The time needed may be kept small i f the query i s s p e c i f i c and many screen b i t s are s e t . Then, because the f i l e s are indexed by an a b b r e v i a t i o n of the screen, i . e . , the p a r t i t i o n i n g f a c t o r , they need not be read completely, thus e l i m i n a t i n g most of the input/output time necessary to read the e n t i r e f i l e . (Of course a d d i t i o n a l time w i l l a l s o be saved because such a s i t u a t i o n w i l l l i m i t the number of i t e r a t i v e matches needed as well.) The worst s i t u a t i o n i s a query so general t h a t the e n t i r e screen f i l e must be read, and most of i t must be searched itérâtively. The time f o r usch a case depends l a r g e l y on the s i z e of the f i l e and the competition for CPU time from other multi-programmed jobs. The estimated worst-case search would r e q u i r e about 35 minutes elapsed time i n an otherwise empty machine, f o r a f i l e of 250,000 s t r u c t u r e s . The economies to be gained by searching many sub-structures at once, i . e . running batch searches, are great. They a r i s e c h i e f l y because the time needed to read the f i l e of s t r u c t u r e s from the d i s k may be apportioned among the sub-structure q u e r i e s . T h i s time i s l a r g e r than the time r e q u i r e d by the i t e r a t i v e searching u s u a l l y needed f o r searches, and thus the time needed to search f o r a batch of 10 sub-structures i s no where near the

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time needed t o do 10 s i n g l e sub-structure searches. For example 10 batched general queries of the worst-case typed noted above should r e q u i r e o n l y about 45 minutes of elasped time. There are two a d d i t i o n a l reasons f o r a batch o f f - l i n e search. F i r s t , the search c r i t e r i a can be expanded to allow searches t h a t are not p o s s i b l e o n - l i n e because of time c o n s i d e r a t i o n s , as i n the case of Boolean combinations of simple fragments, or a v a i l a b l e computer resources, as i n the case o f c r i t e r i a based on n o n - s t r u c t u r a l information that i s s t o r e d on other f i l e s . The second reason f o r batch searching i s based on the need t o e f f i c i e n t l y handle l a r g e numbers of queries and answers which r e q u i r e a source of high-volume hard copy output. A l l searches, whether f o r o n - l i n e or batch p r o c e s s i n g , may be formulated i n t e r a c t i v e l y . The s t r u c t u r e fragments are gen erated on the IMLAC t e r m i n a l and e d i t e d o n - l i n e . I f erroneous, they are immediately returne d e f i n e and e d i t a l l th l i n e , and be sure they are a t l e a s t i n the c o r r e c t syntax. This c a p a c i t y i n c r e a s e s the e f f e c t i v e n e s s of the batch search by e l i m i n a t i n g long delays i n turn-around due to input e r r o r s . Indi v i d u a l fragments, with no Boolean combinations, may be used f o r a p r e l i m i n a r y search o n - l i n e . Thus the user has the c a p a b i l i t y of formulating a query and l o o k i n g at a predetermined number of answers. Based on t h i s "preview" the user may then submit the query t o the batch search, r e d e f i n e the search c r i t e r i a and look at a r e v i s e d set o f answers, or d e l e t e the query e n t i r e l y . This preview c a p a b i l i t y may i n f a c t prove to be the most u s e f u l f u n c t i o n o f the o n - l i n e sub-structure search. The batch search a l s o contains the c a p a c i t y to search by a s p e c i f i e d molecular formula. T h i s c a p a b i l i t y was not i n c l u d e d i n the o n - l i n e search because there was no requirement f o r i t . Batch search output i s p r i n t e d o f f - l i n e on a Versatec e l e c t r o s t a t i c dot matrix p r i n t e r / p l o t t e r . It prints 100 dots per i n c h and uses 11 i n c h wide paper which i s e a s i l y i n c o r p o r a t e d into reports. B i o l o g y and Inventory Subsystems. These subsystems are only searched i n batch mode. Quick access i s provided by p e r i o d i c COM l i s t i n g s i n a c c e s s i o n number and sample number sequences. Be cause o f the s i z e of the f i l e s , simple queries ( i . e . what i s the m a l a r i a screening data f o r compound A or how much of compound Β do we have on hand) are most e f f i c i e n t l y and economically handled with m i c r o f i l m . More complex searches and searches r e q u i r i n g i n t e r a c t i o n among the sub-systems r e q u i r e s u f f i c i e n t computer resources t o p r o h i b i t running during prime time on a m u l t i programmed computer. While e i t h e r the B i o l o g y or Inventory subsystems may be searched independently, i n p r a c t i c e t h i s i s seldom done. More o f t e n , i n f o r m a t i o n from more than one system must be found i n

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order t o answer a query. I f the search begins with the Biology system the SUBSET command provides the i n t e r f a c e with the other systems by generating a f i l e o f answers with can be used as input t o continue the search. For example a search such as SUBSET, BIOREC, WHERE, BIOSOURCE = 2300 AND, BIOPGS = G, OR, BIOSOURCE = 2300, AND, BIOPGS = P. would create a f i l e o f b i o l o g y records where the source o f the compounds was 2300 and the type was e i t h e r Ρ (purchased) o r G (gift). T h i s f i l e could then be used, f o r example, t o f i n d a d d i t i o n a l samples o f the same compounds from other sources. The SUBSET, USING command permits the output o f one search t o be used as the c o n t r o l l i n g f a c t o r t o a second search. A r e c o r d i s read from the u s i n g f i l e , the key i s e x t r a c t e d from the r e c o r d and i s used t o perform a rando r e c o r d i s found the a d d i t i o n a i f these c r i t e r i a are met, a new subset f i l e i s created from the matched r e c o r d s . F o r example: SUBSET, USING, FILA, CIS, WHERE, AMTON= 500 M, AND, ARRAY (ALL) NOT = MM. The p r e v i o u s l y r e t r i e v e d b i o l o g i c a l data s u b - f i l e would be used t o query the inventory f i l e . Once matching records ( i . e . records with the same sample number) were found they would be checked f o r an amount on hand equal t o o r greater than 500 mg and no shipment t o t e s t system MM. I f these c r i t e r i a are met, the matching inventory records are used t o create a new SUBSET f i l e . The search may then continue t o o b t a i n a d d i t i o n a l information from the chemistry f i l e s . The Report Generator would then pro cess a l l appropriate SUBSET f i l e s according t o c r i t e r i a s p e c i f i e d by the user t o generate the f i n a l r e p o r t . Search S t r a t e g i e s As i n d i c a t e d e a r l i e r , most searches r e q u i r e accessing more than one data base. There are no r u l e s governing the sequence i n which the d i f f e r e n t subsystems must be searched. The output from a search o f any system can be used, through the SUBSET USING command, as c r i t e r i a o r p a r t i a l c r i t e r i a f o r searching any other subsystem. The outcome o f any given search should be the same r e g a r d l e s s o f which system i s used t o begin the search. However, the amount o f computer time r e q u i r e d t o complete a given search may i n f a c t depend on the sequence i n which the systems are searched. In general i t i s best t o begin a search on the system which w i l l be most r e s t r i c t i v e i n the number o f responses. However, the determination o f that system i s not always obvious and r e q u i r e s a f a i r degree o f f a m i l i a r i t y with the contents as w e l l as the o r g a n i z a t i o n o f the data bases. For example, suppose a user wishes t o send t o t e s t system Β a l l q u i n o l i n e d e r i v a t i v e s t h a t are a c t i v e i n t e s t system A. In a d d i t i o n , t e s t system Β

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r e q u i r e s a minimum q u a n t i t y of 700 mg to complete the t e s t and the user does not wish t o deplete the t o t a l inventory supply. The search c r i t e r i a then a r e : Biology subsystem search: SUBSET,BIOREC,WHERE,LABID=TSA. Inventory subsystem search: SUBSET,INVREC,WHERE,LABID(ALL),N0T=TSB, AND, QUANT, NOT 1000 mg Chemistry subsystem search: Structure= Ζ Ζ

ζ The user must r e a l i z inventory system w i l l not provide a s a t i s f a c t o r y answer since the inventory system i s sequenced by sample number. Even though an i n d i v i d u a l sample may appear t o meet the inventory c r i t e r i a i t i s necessary t o know the p e r t i n e n t accession numbers so that i n ventory data f o r a l l samples o f a given compound may be compared a g a i n s t the inventory c r i t e r i a together. That i s , i f any one sample o f a compound with m u l t i p l e inventory e n t r i e s has been shipped t o TS Β then a l l samples of the same compound, r e g a r d l e s s of shipping data, should be r e j e c t e d by the search. The search cannot do t h i s u n t i l i t has the necessary information to c o r r e l a t e sample data. S i m i l a r l y the d e c i s i o n t o begin with e i t h e r of the remaining systems r e s t s on the user's knowledge o f the data. That i s , i f there are a l a r g e number o f q u i n o l i n e s on the s t r u c t u r e f i l e and t e s t system A i s a small l a b o r a t o r y with r e l a t i v e l y few a c t i v e s , i t would be p r e f e r a b l e t o s t a r t the search with the b i o l o g y system. I f the sub-structure c r i t e r i a o f the chemistry p o r t i o n o f the search are r e l a t i v e l y s p e c i f i c then, because o f the speed o f the search, i t may be d e s i r a b l e to s t a r t with the chemistry search. The f e a s i b i l i t y o f programming a master search which would accept f r e e t e x t search c r i t e r i a from the user and c o n s t r u c t a search s t r a t e g y i s being s t u d i e d . F i r s t however, more user ex p e r i e n c e i n the development o f e f f e c t i v e search s t r a t e g i e s i s necessary. The Report Generator contains a d d i t i o n a l options open t o the user which are not p r e c i s e l y search c r i t e r i a . Because o f the p r o p r i e t a r y nature o f much o f the data base, unless the user s p e c i f i c a l l y i n d i c a t e s otherwise, only open (non-proprietary) data w i l l be reported. I t i s a l s o p o s s i b l e f o r the user to s p e c i f y a l l h i t s on a combined search be reported r a t h e r than o n l y matched h i t s . For example the chemistry data base could be searched f o r t r i a z i n e s and the output used t o search the b i o l o g y data base f o r m a l a r i a a c t i v e s . The user has the o p t i o n o f spec i f y i n g t h a t o n l y those t r i a z i n e s t h a t show m a l a r i a a c t i v i t y be

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r e p o r t e d o r t h a t a l l t r i a z i n e s along with any a v a i l a b l e data showing m a l a r i a a c t i v i t y be reported. The user may s p e c i f y t h a t only data w i t h i n a c e r t a i n range of a c c e s s i o n numbers or sample numbers be reported, or that only data r e c e i v e d w i t h i n a s p e c i f i c time span be reported. In add i t i o n the user may s p e c i f y the sequence of the data i n the report. Applications The CIRS i s used by the D i v i s i o n o f Experimental Therap e u t i c s i n support o f a l a r g e drug development program. The R e t r i e v a l System (as separate from the s t r u c t u r e r e g i s t e r y and data maintenence system) i s r o u t i n e l y used f o r a v a r i e t y of f u n c t i o n s . A n a l y s i s o f Research Proposals Development Command supports research i n the d i r e c t e d s y n t h e s i s of screening candidates. Twice y e a r l y the D i v i s i o n of E x p e r i mental Therapeutics reviews synthesis proposals. The proposed s t r u c t u r e s i n each p r o p o s a l are entered i n t o the data base i n the "XR" s e r i e s and are a l s o entered as i d e n t i t y searches to determine whether o r not the compounds are already on hand and to i d e n t i f y d u p l i c a t i o n among the proposals. In a d d i t i o n , subs t r u c t u r e searches f o r the major c l a s s e s o f compounds proposed are a l s o run. Matches from both the i d e n t i t y and sub-structure searches are then used to query the b i o l o g y and inventory f i l e s . The reviewer i s presented with a r e p o r t sequenced by proposal number p r o v i d i n g him with a l l a v a i l a b l e information on the a v a i l a b i l i t y and a c t i v i t y o f a l l s p e c i f i c compounds and c l a s s e s o f compounds i n each p r o p o s a l . A s i m i l a r procedure i s used by cont r a c t monitors t o review progress on synthesis c o n t r a c t s and to prevent d u p l i c a t i o n o f e f f o r t . Review o f Screening Data. S t r u c t u r e s are added to the screening data a f t e r the data are r e c e i v e d from the l a b o r a t o r i e s . The screening data simply a c t as whole s t r u c t u r e queries to the chemistry r e t r i e v a l system. The r e p o r t i s sequenced by a c c e s s i o n number so t h a t data f o r d u p l i c a t e samples w i l l be grouped t o gether. Sub-structure searches can be formulated from the r e p o r t to i d e n t i f y a d d i t i o n a l samples e i t h e r on hand or i n p r e p a r a t i o n i n those c l a s s e s o f compounds t h a t are i n t e r e s t i n g . The matches from the sub-structure search can then be used to f u r t h e r query the b i o l o g y and inventory f i l e s to determine i f those a d d i t i o n a l samples i d e n t i f i e d have already been screened, i f so t h e i r a c t i v i t y , i f not the amount a v a i l a b l e , and a p o s s i b l e source f o r obtaining additional material. Monitoring o f Screening L a b o r a t o r i e s . The system i s used to determine c o r r e l a t i o n o f a c t i v i t y between primary and secondary

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

12.

PAGE ET AL.

Integrated Data Retrieval System

199

screens for the same disease and between basic screens for d i f ferent diseases. It is also used to determine samples with sufficient quantity for screening when a new test system is being developed. It can be used to moniter ongoing a c t i v i t y . For example the user could request a report on a l l samples shipped to a given test system for which no biological data has been reveived. Conclusion The chemical-biological data system has been an integral part of the Army's drug development program for over 12 years. The current up-grading of the original system w i l l eliminate the labor-intensive maintenance of manual f i l e s , allow closer mon itoring of a l l aspects of the program and provide information in a more timely manner. Thos particularly attractiv output, machine coding of sub-structure queries, on-line editing of queries, and user designed reports which provide correlated data from a l l data f i l e s . References 1.

D. P. Jacobus et. al., "Experience with Mechanized Chemical and Biological Information Retrieval Systems." J. Chem Doc Vol 10, ρ 135, 1970.

2.

J . A. Page, R. Theisen, F. Kuhl, Manuscript in preparation.

3.

A. Feldman, "An Efficient Design for Chem Structure Searching. I. The Screens." J . Chem. Info. and Comp. Sciences, Vol 15, No. 3, 1975.

4.

L . Hodes and A. Feldman, "An Effective Design for Chemical Structure Searching. II. F i l e Organization". J. Chem. Info. and Comp. Sciences, in press May 78.

5.

A. Feldman, "An Efficient Design for Chemical Structure Searching. III. The Coding of Resonating and Tautomeric Forms. J. Chem Info and Comp. Science, Vol 17, No. 4, 1977.

6.

A. Feldman, "A Chemical Teletype." J. Chem. Doc., Vol 13, No. No. 2, 1973.

7.

A. N. De Mott, "Interpretation of Organic Chemical Formulas by Computer", IEEE Spring Joint Computer Conf, 1968, ρ 61.

RECEIVED August 29,

1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13

The

Drug

Research and D e v e l o p m e n t

I n f o r m a t i o n S y s t e m of N C I ' s Therapeutics

Chemical

Developmental

Program

SIDNEY RICHMAN, GEORGE F. HAZARD, JR., and ALICE K. KALIKOW Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, MD 20014 The Developmental of Cancer Treatment responsible for all preclinical phases i n the development of cancer t h e r a p e u t i c agents. As one approach to i d e n t i f y i n g leads to such drugs, the DTP (which subsumed the Drug Research and Development Program(1)) acquires drugs, s y n t h e t i c m a t e r i a l s and n a t u r a l products and t e s t s these m a t e r i a l s i n a v a r i e t y of antitumor systems. Since the i n c e p t i o n of the NCI cancer chemotherapy activity i n 1956, some 316,000 chemicals and drugs have been screened i n approximately 4,000,000 animal and in-vitro tests. Currently, 15,000 such m a t e r i a l s are acquired and evaluated y e a r l y . E v o l u t i o n of the System As in other biological screening programs, the supporting chemical i n f o r m a t i o n system (CIS) must p r o v i d e , at a minimum, two basic capabilities: the registration of a c q u i s i t i o n s and access to the data base. The chemical system which was s t a r t e d in 1956 employed a manual r e g i s t r a t i o n procedure based on c a t a l o g i n g compounds by molecular formula and d i f f e r e n t i a t i n g between compounds having the same molecular formula by the systematic chemical name. Systematic names for accessions were maintained on punched paper tape. Substructure searching f o r analogs was based on chemical fragment codes assigned to accessions and an o p t i c a l coincidence system used for r e t r i e v a l . ( 2 ) The second system, used from 1967 through 1974 c o n s i s t e d essentially of three components: the Chemical A b s t r a c t s S e r v i c e (CAS) R e g i s t r y System ( 3 , 4 , 5 ) as adapted f o r NCI p r i v a t e use; CAS' automated batch substructure search procedures (6,7); and computer-generated indexes for identifying substances by systematic name. The passage of the N a t i o n a l Cancer Act of 1971 r e s u l t e d i n an increased y e a r l y a c q u i s i t i o n r a t e which rose i n three years from a

This chapter not subject to U.S. copyright. Published 1978 American Chemical Society In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13.

RiCHMAN E T A L .

NCfs

Chemical

Information

System

201

l e v e l of 10,000 chemicals and drugs t o 39,000. With a f i l e size of 158,000 substances and complex manual procedures r e q u i r e d d e s p i t e the automated processing of accessions described above, i t was evident t h a t there was need f o r a CIS more responsive t o operational requirements. I n June, 1971 the U n i v e r s i t y o f Pennsylvania, under an NCI c o n t r a c t , began t h e design and implementation of DTP s Drug Research and Development Chemical Information System (DR&D CIS) w i t h a d d i t i o n a l programming support provided by E.I. Dupont de Nemours and Company under subcontract. In J u l y , 1974, t h i s new system was i n s t a l l e d a t t h e Chemical A b s t r a c t s S e r v i c e (CA) which operates the system under an NCI contract. The INVENTORY and SPECIAL STRUCTURAL FEATURE IDENTIFICATION processors were added t o the CIS i n February, 1976 and September, 1977 r e s p e c t i v e l y . 1

Design C o n s t r a i n t s The c o n s t r a i n t s on the design were t o avoid r e s e a r c h , use e x i s t i n g systems o r programs wherever p o s s i b l e , and be compatible w i t h the CAS environment t o f a c i l i t a t e o p e r a t i o n of t h e e x i s t i n g and planned CAS chemical i n f o r m a t i o n handling techniques. The f o l l o w i n g components were obtained from other systems and were i n t e g r a t e d (sometimes w i t h m o d i f i c a t i o n s ) i n t o the t o t a l system: CAS Data Management System (FIDO) (8.) ; CAS R e g i s t r y I I I (9,10,11); CAS Transaction E d i t o r ; DCRT (NIH) On L i n e S t r u c t u r e Input System f o r query f o r m u l a t i o n (12); General processing u t i l i t i e s and a macro processor from Dupont; U.S. Army CIDS Substructure Ring Screens and I n t e r a c t i v e Search (1_3); CAS A l g o r i t h m i c S t r u c t u r e D i s p l a y (ASD) (14); and CAS On Line S t r u c t u r e Input System (L5) f o r input t o R e g i s t r y . 1

1

I n t e r a c t i o n of the CIS w i t h A c c e s s i o n i n g and Screening 1

F i g u r e 1 o u t l i n e s the r o u t i n e i n t e r a c t i o n of DTP s chemical and drug a c c e s s i o n i n g and screening a c t i v i t i e s (which are h e a v i l y c o n t r a c t supported) w i t h the chemical and b i o l o g i c a l data processing systems. Samples of compounds a r e submitted by s u p p l i e r s or are c o l l e c t e d a t s u p p l i e r s ' s i t e s . Accompanying the samples are data sheets which i n c l u d e the s t r u c t u r a l and s u p p l i e r identification and o c c a s i o n a l l y biological and physical properties. The A c q u i s i t i o n a c t i v i t y weighs and t e m p o r a r i l y s t o r e s t h e sample, prepares and t r a n s m i t s the input documents (which i n c l u d e s t r u c t u r a l and n o n - s t r u c t u r a l data) t o the Chemical Information P r o c e s s i n g a c t i v i t y , and awaits the r e t u r n of 21 a c t i o n and i n f o r m a t i o n a l system outputs. Reports a r e forwarded t o s u p p l i e r s a d v i s i n g them of the accession numbers assigned t o t h e i r submissions o r requesting the replenishment of supply f o r a previous submission t o complete t e s t i n g . Bottle labels are

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

9

SUPPLIER

Sample with Data Sheet

Inquiry

Reports

Sample with transfer and Shipping Documents

Figure 1.

Test Results

Information on Receipts, Shipments, and Replenishments

DTP STAFF

Shipping Instructions

STORAGE AND DISTRIBUTION

Inquiry

/BIOLOGY \ DATA Ν PROCESSING , SYSTEM / \ (BDPS) / /

Inquiry

Reports

SCREENING SUPPORT

BIOLOGY INFORMATION PROCESSING

JG) SCREENING

Test Results

BIOLOGY \ DATA > PROCESSING . SYSTEM j \ (BDPS) / f

/

Receipt Advice and Return of Samples

Samples with Shipping Documents

Shipping Transactions

'CHEMICAL ^INFORMATION} ^SYSTEM (CIS)/

Interaction of accessioning and screening with data processing

CHEMICAL \ INFORMATION) .SYSTEM (CIS)/

CHEMICAL INFORMATION PROCESSING

Outputs

Inputs

ACQUISITION

Accession Reports and Replenishment Requests

Ο

I

> r

ο

Μ §

ο χ

> r

η 3

α

M

Ι Ο

>

<

to

13.

RiCHMAN E T A L .

NCI's

Chemical

Information

203

System

a f f i x e d t o the samples which are t r a n s f e r r e d to t h e Storage and D i s t r i b u t i o n a c t i v i t y w i t h advice on c o n d i t i o n s f o r storage and s h i p p i n g and w i t h computer-generated manifests f o r s h i p p i n g samples to Screening L a b o r a t o r i e s f o r r o u t i n e b i o l o g i c a l t e s t i n g . Among the v a r i e t y of outputs used by the DTP s t a f f i s the request that s p e c i a l t e s t i n g be scheduled f o r a sample i d e n t i f i e d by the system t o be an analog of program i n t e r e s t . (See Table 1 f o r a d e s c r i p t i o n o f s e l e c t e d system outputs.) The CIS t r a n s f e r s t o the B i o l o g i c a l Data P r o c e s s i n g System (BDPS) i n f o r m a t i o n in a machine-processable form regarding the r e c e i p t o f samples (both new t o the c o l l e c t i o n or d u p l i c a t e s o f p r e v i o u s a c q u i s i t i o n s ) , shipments made, and replenishment a c t i o n s . The Screening Support a c t i v i t y queries the BDPS t o secure and review p r i o r t e s t i n g f o r newly-received d u p l i c a t e s and r e f i l l s and t o decide on the need for a d d i t i o n a l t e s t i n g . When t h e Storag manually-prepared shippin of Program i n t e r e s t f o r s p e c i a l t e s t i n g or f o r reshipments, t h e chemical f i l e i s queried t o secure the q u a n t i t y remaining i n s t o c k , storage l o c a t i o n , and s p e c i a l i n s t r u c t i o n s r e g a r d i n g t h e conditions of shipment, storage, and t e s t i n g . Transactions regarding shipments and r e t u r n s a r e input and e d i t e d o n - l i n e ; however, t h e f i l e i s updated i n a batch mode. Records of a c t i o n to secure an a d d i t i o n a l supply of a compound a r e input and communicated t o the BDPS as w e l l as advice on the r e c e i p t of refills The Screening l a b o r a t o r i e s acknowledge t h e r e c e i p t of shipments, t e s t the compounds, forward the r e s u l t s t o the BDPS, and r e t u r n the excess supply t o the Storage and D i s t r i b u t i o n activity. The BDPS outputs summaries of the t e s t r e s u l t s which are d i s t r i b u t e d to s u p p l i e r s , s c r e e n e r s , and the DTP s t a f f . F i l e Structure F i g u r e 2 i l l u s t r a t e s the r e l a t i o n s h i p among t h e p r i n c i p a l f i l e s of the system, as w e l l as the h i e r a r c h i c a l s t r u c t u r e of the NSC Cross Reference f i l e . The NSC Number i s a unique serial number machine-assigned t o each compound. Because of c o n f i d e n t i a l i t y requirements, a d i f f e r e n t NSC Number i s assigned to a substance submitted by an i n d u s t r i a l s u p p l i e r which has the same s t r u c t u r e as a sample p r e v i o u s l y submitted by another i n d u s t r i a l s u p p l i e r . The s t r u c t u r e r e p r e s e n t i n g the compound i s r e g i s t e r e d by the NCI v e r s i o n of the CAS R e g i s t r y I I I System o n l y once under a separate but unique r e g i s t r y number c a l l e d t h e IRN ( I n t e r n a l R e g i s t r y Number, not t o be confused w i t h CAS R e g i s t r y Number) and the connection t a b l e i s s t o r e d i n t h e NCI R e g i s t r y Structure f i l e (and the R e g i s t r y Ring f i l e ) . A l l the other data p e r t a i n i n g to a compound submission, i n c l u d i n g the IRN, i s i n t h e 1

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

204

Special Handling Text

Supplier Name/Address

Connection Table

f REGISTRY ι STRUCTURE/ AND RING I I FILES \

O F MEDICINAL

CHEMICAL

Shipping Box Contents

(

MISCELLANEOUS FILE

Special Handling Code

Supplier Code

—ι—

INFORMATION

Search Keys I t f SEARCH INDEXES AND INVERTED ι LISTS NSC Number

Shipping List Number

NSC CROSS REFERENCE FILE I I I NSC * NUMBER LU

Ζ DECLASSI FICATION STATUS

SAMPLE*

SAMPLE PROCESSING STATUS

STRUCTURAL' IMAGE

SAMPLE SHIPPING

•Records displayable in the interactive Inquiry Subsystem.

Figure 2.

File rehtionships in the DR 6- D CIS

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13.

RICHMAN

ETAL.

NCVs

Chemical

Information

System

205

Cross Reference f i l e . The connection t a b l e i n the R e g i s t r y S t r u c t u r e f i l e i s accessed f o r a given NSC Number by t h e IRN present i n the NSC record of the Cross Reference f i l e . The name and address and other c o n t r o l i n f o r m a t i o n f o r a given s u p p l i e r i n the M i s c e l l a n e o u s f i l e i s accessed by the s u p p l i e r code i n the NSC record f o r a given compound. The NSC Numbers of a l l the compounds scheduled f o r shipment on a s p e c i f i c M a t e r i a l Shipping L i s t (MSL) i s accessed f o r a s p e c i f i c carton of samples by the MSL number i n the MSL r e c o r d i n the Miscellaneous f i l e . As w i l l be d e s c r i b e d l a t e r , the INQUIRY subsystem uses the search indexes and i n v e r t e d l i s t s t o be l e a d t o NSC Numbers and t h e i r a s s o c i a t e d data i n response t o f u l l s t r u c t u r e o r s u b s t r u c t u r e searches. (See Table 2 for the s i z e and growth r a t e of the DR&D CIS f i l e s . ) The h i e r a r c h i c a l NSC Cross Reference f i l e has a t i t s h i g h e s t l e v e l the NSC Number r e c o r d , c o n t a i n i n g only NSC-related data such as IRN, c o n f i d e n t i a l i t y antitumor a c t i v i t y , compoun h i e r a r c h y contains four record types. The Sample record r e l a t e s to s p e c i f i c samples of the NSC, c o n t a i n i n g f o r each sample such data as s u p p l i e r code, s u p p l i e r compound i d e n t i f i c a t i o n and l o t number, weight, e t c . The QNS (Quantity Not S u f f i c i e n t ) r e c o r d r e l a t e s t o replenishment a c t i o n s when a d d i t i o n a l m a t e r i a l i s r e q u i r e d t o complete t e s t i n g . The D e c l a s s i f i c a t i o n r e c o r d d e a l s with actions pending regarding the d e c l a s s i f i c a t i o n o f c o n f i d e n t i a l submissions. The S t r u c t u r e Image record c o n t a i n s t h e molecular formula and the s t r u c t u r a l image of the compound which i s stored only once f o r a group of NSC records having t h e same s t r u c t u r e . The t h i r d l e v e l of the h i e r a r c h y below t h e Sample record has two record types, each of which may have m u l t i p l e records. The Sample Processing Status record c o n t a i n s i n f o r m a t i o n regarding the s t a t u s of a given sample as i t t r a v e r s e s through t h e DR&D CIS. When the processing of the sample i s complete, t h e s t a t u s record i s d e l e t e d . The Sample Shipping r e c o r d c o n t a i n s data regarding each shipment of the sample, such as t h e amount shipped and t o whom. The System as a Network of Processors As i l l u s t r a t e d i n F i g u r e 3, the DR&D CIS may be represented as nodes i n an interconnected network. The b l o c k s i n t h e f i g u r e represent computer jobs (each w i t h one or more p r o c e s s i n g steps) that a r e c a l l e d processors. A processor r e c e i v e s t r a n s a c t i o n s v i a manual e n t r y through an e d i t o r (E i n p u t s ) or v i a another processor (P i n p u t s ) . The a p p l i c a t i o n program (or programs) w i t h i n a processor r e l a t e s t o a s p e c i f i c set of f u n c t i o n s performed on a s e r i e s o f t r a n s a c t i o n types. A s s o c i a t e d w i t h each processor a r e a v a r i e t y of man/machine i n t e r a c t i o n s which may be f u n c t i o n a l l y and o r g a n i z a t i o n a l l y subdivided f u r t h e r . Such s u b d i v i s i o n s a r e c a l l e d s t a t i o n s , analogous t o work s t a t i o n s i n a production p l a n t . Twenty-one work s t a t i o n s a r e mapped on t o processors i n t h e

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL

206

Table 1.

O F MEDICINAL

CHEMICAL

INFORMATION

Selected System Outputs and Their Use

Β and 1 D Record Journals - data automatically transmitted to update the BDPS with data regarding shipments, testing scheduled, second suppliers, and replenishment actions. Biology Inquiry Listing - data on duplicate samples and refills used in the BDPS to secure test results from previous samples and to schedule additional testing. Bottle Labels - used to identify the contents of the shipping and reference bottles. Chemistry Card — basic manual reference for accessions, including information such as structural diagrams and chemical class of interest. Drug Transfer Record - manifest of materials to be transferred from Acquisition activity to the Storage and Distribution activity, including instructions for distribution. Inventory Exception Report — advice of the need to replenish the supply of positive control compounds when reorder levels are reached. Material Shipping List - manifests of compounds to be shipped to Screeners for routine screening. Name and Address Card — reference information of suppliers and screeners. NSC Number List - advice to suppliers of the NSC (accession) Numbers assigned to their submissions, including structures. Refill Report - periodic report of refills received to assure prompt shipment. Request for Manual Material Shipping List - request for scheduling special testing of a material identified to be an analog of Program interest. Request for Declassification - request for a supplier to authorize the release of information of a confidential sample, e.g., for publication. Screener Receipt Overdue Report - to assure the receipt of shipment to screeners.

Table2. DR&D CIS File Sizes' File Name',(a)

Current Size (Megabytes)

Annual Increase (Megabytes)

Cross Reference Extended Molecular Formula Index Ring ID Miscellaneous Statistics Chem Search Index IRN/NSC* Index NSC* Inverted List NSC* Bit map Registry Structure Registry Ring Transaction File

1 9 1 . .0

17.0

16..5

0.8

2..9

0.2

TOTAL

2..4

0.2

0..2

0.0

1..9

0.1

19..1

0.8

4..6

0.2

11..6

0.5

9 6 . .7

4.5

5..9 1 0 0 . .0

0.5

4 5 2 . .8

24.8

0.0

a

* 'ln addition to the listed files which reside on disk, two master files reside on tape; the NSC'/Key file is contained on eight reels and the Key/NSC" is contained on two reels of tape. The increase in file size is based on the accession of 15,000 new compounds annually.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

Processor network of the DR ù D CIS Figure 3.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

208

RETRIEVAL

OF

MEDICINAL

CHEMICAL

INFORMATION

system. (For example, the NSC Assignment processor has three such work s t a t i o n s : D e c l a s s i f i c a t i o n D e c i s i o n , r e q u i r i n g communication w i t h s u p p l i e r s ; NSC D e c i s i o n , r e q u i r i n g DTP a c t i o n based on the review of i n f o r m a t i o n regarding d u p l i c a t e s ; and NSC Assignment, a programmed d e c i s i o n f o r most cases based on the uniqueness of the s t r u c t u r e , s u p p l i e r i n f o r m a t i o n , and confidentiality.) Data regarding samples are processed through d i f f e r e n t paths depending on the c o n d i t i o n s of the submission (e.g., c o n f i d e n t i a l versus n o n - c o n f i d e n t i a l ) and c h a r a c t e r i s t i c s of the compound i t s e l f (e.g., s t r u c t u r e new to the f i l e versus a d u p l i c a t e of a previous a c c e s s i o n ) . Thus, a new submission must go through R e g i s t r y but a r e f i l l does not. A p a r t i c u l a r t r a v e r s a l through the s t a t i o n s of the system i s c a l l e d a journey. The DR&D CIS has fourteen processors, twenty-one work s t a t i o n s , and t h i r t e e n journeys. A system c o n t r o l program c a l l e d IRAC monitors the processing of sample data through th v a r i o u s t a t i o n r e q u i r e d b th d i f f e r i n journeys. For every journe the Sample Processing f i l e which contains the combination of s t a t u s codes f o r each of the s t a t i o n s appropriate f o r the journey of the accessed sample through the system. Every submission i s examined p e r i o d i c a l l y by a program which reads i t s s t a t u s r e c o r d , compares the current date w i t h i t s expected completion time at each s t a t i o n and r e p o r t s any that i s overdue. A second c o n t r o l mechanism l i s t s every sample i n process as an a r r a y of s t a t u s codes at each appropriate s t a t i o n for each journey. These r e p o r t s are used to oversee and manage the system by i d e n t i f y i n g e x i s t i n g and p o t e n t i a l b o t t l e n e c k s . A b r i e f d e s c r i p t i o n of the b a s i c programs or processors follows. LOGIN - inputs n o n - s t r u c t u r a l i n f o r m a t i o n regarding compound samples. STRUCTURE INPUT AND EDIT - converts to a connection t a b l e s t r u c t u r a l data input by a chemical t y p e w r i t e r or other input devices and e d i t s the s t r u c t u r a l diagram f o r chemical validity. REGISTRY - i d e n t i f i e s whether the s t r u c t u r e of an accession i s unique to the R e g i s t r y S t r u c t u r e f i l e and updates this f i l e . NSC ASSIGNMENT - assigns an NSC Sample Number depending on the uniqueness of the s t r u c t u r e , s u p p l i e r i n f o r m a t i o n , and c o n f i d e n t i a l i t y . SSFID - i d e n t i f i e s by i t e r a t i v e search accessions which r e q u i r e s p e c i a l t e s t i n g because they are analogs of compounds of i n t e r e s t to the DTP Program. KEY ASSIGNMENT assigns structure fragments and chemically d e s c r i p t i v e keys to accessions to permit querying the f i l e . CHEM SEARCH INDEX - updates the search index w i t h the assigned keys. COMMUNICATIONS - generates a c t i o n and informational reports r e q u i r e d by the a c c e s s i o n i n g and screening a c t i v i t i e s . BI01, BI02, BI03 and BI04 - generate i n a machine-processable form v a r y i n g data r e q u i r e d by the B i o l o g i c a l Data Processing System. INVENTORY - enables the updating of inventory data and generates manifests to s h i p new r o u t i n e accessions f o r screening. CROSS REFERENCE UPDATE - updates the Cross Reference f i l e . The INQUIRY and LOGX processors w i l l be described as part of the I n q u i r y

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13.

RiCHMAN E T A L .

NCI's

Chemical

Information

209

System

Subsystem which f o l l o w s . I n q u i r y System The CIS I n q u i r y subsystem was designed t o be totally i n t e g r a t e d i n t o the p r o c e s s i n g system and to use s t a t e of the a r t techniques to a l l o w users to r e g a i n the " f e e l " f o r the f i l e lost i n the previous batch system w h i l e r e t a i n i n g the f l e x i b i l i t y and accuracy that i t e r a t i v e (atom by atom) searching of a d e t a i l e d connection table allowed. The system developed uses data e x t r a c t e d from the s t r u c t u r a l and n o n - s t r u c t u r a l data f i l e s and indexes i t i n such a way that o n - l i n e , i n t e r a c t i v e searching from a remote t e r m i n a l i s p r a c t i c a l . Development of Search Keys. An a n a l y s i s was made of previous DTP searches (16), an e f f e c t i v e use of th R e g i s t r y I I I connection t a b l e . Although some thought was given t o developing novel s u b s t r u c t u r e search keys, t h e r e a l i t y of our development schedule l e d to the use of a combination of p r e v i o u s l y developed key types that have been found e f f i c i e n t . F i g u r e 4 shows a m y t h i c a l example of an abbreviated DTP s t r u c t u r e record and sample o f each type of search key. A d e s c r i p t i o n of each follows. Augmented Atom (AA). This atom centered fragment i s based on the concept used by CAS and o t h e r s . (17 _18) Each non-hydrogen atom of a compound and i t s neighbors together w i t h the corresponding bonding i n f o r m a t i o n generates an AA key and these l a r g e keys are e x h a u s t i v e l y broken i n t o smaller keys, the s m a l l e s t being atom p a i r s . Occurrence counts are c a l c u l a t e d and are a s s o c i a t e d w i t h each NSC. J

Ring System Keys. Since R e g i s t r y I I I connection t a b l e s are segmented i n t o an a c y c l i c and a r i n g p o r t i o n , r i n g keys are only assigned f o r the f i r s t occurrence of a r i n g system and stored. Thereafter, t h e a p p r o p r i a t e r i n g keys are r e t r i e v e d during key generation using the r i n g i d e n t i f i e r . The f o l l o w i n g three keys are defined f o r every r i n g system i n a compound: Nucleus Keys (NUC). This key i s generated from molecular formula of each complete c y c l i c nucleus i n a substance. Two t o t a l s of c e r t a i n bond types q u a l i f y t h i s moleform: the sum of a l t e r n a t i n g and d e l o c a l i z e d bonds; and the sum of tautomeric, double and t r i p l e bonds. Occurrence counts o f a given key are a l s o generated f o r each NSC and s t o r e d . In F i g u r e 4, there i s a t o t a l of s i x a l t e r n a t i n g bonds i n the pyrimido r i n g of purine once these bonds have been normalized by R e g i s t r y I I I a l g o r i t h m s . One double bond i n the fused imidazo r i n g p l u s an a l t e r n a t i n g bond a t the f u s i o n p o i n t gives a (6,JO q u a l i f i c a t i o n to the element count.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13.

RICHMAN

ETAL.

NCVs

Chemical

Information

System

211

Ring Keys (RIN). This key c i t e s the molecular formula for each i n d i v i d u a l r i n g i n the s m a l l e s t set of s m a l l e s t r i n g s (SSSR), p l u s those other r i n g s o f l e s s than or equal t o e i g h t atoms. Bonding q u a l i f i c a t i o n i s the same as i n the NUC key. RSIZE (RSI) Key. This key c i t e s i n ascending order t h e sequence of r i n g s i z e s i n the SSSR. One RSIZE key per r i n g system i s assigned although occurrence counts w i t h i n a compound are kept. In F i g u r e 4, the purine r i n g has an RSI=5,6 and furan has RSI=5.

presence tritium.

Element Keys (ELE). One key i s generated f o r t h e of each element i n the p e r i o d i c t a b l e p l u s deuterium and No occurrence counts are kept f o r t h i s key.

M i s c e l l a n e o u s Keys (MISC) These a r e a mixture of non-structural and s t r u c t u r a submitted data. As see generated f o r such data as the presence of a type 5 s t e r e o d e s c r i p t o r (carbohydrate or amino a c i d ) , a d e s i g n a t i o n of DTP biological interest (SAC) and the s u p p l i e r code o f the submitter (sup 240A). In a d d i t i o n f o r compounds w i t h no s t r u c t u r e c l a s s d e s i g n a t i o n , keys such as " A l k a l o i d " are assigned manually f o r compounds which cannot be machine r e g i s t e r e d . Extended Molecular Formula (EMF). This search key c o n s i s t s of the molecular formula of each fragment i n a compound, q u a l i f i e d by t h e number of prime r i n g s i n that moleform and the number of d i r e c t non-hydrogen atoms attached to r i n g s . Search F i l e O r g a n i z a t i o n . Search keys a r e s t o r e d i n t h e Chemsearch Index F i l e . To a l l o w easy access to the approximately 15,000 keys generated by our open ended fragment generation and t o g i v e a user the o p p o r t u n i t y t o e i t h e r use the e x t e n s i v e bonding i n f o r m a t i o n o r ignore i t , the keys are s t o r e d as i n v e r t e d l i s t s and are indexed using a v a r i a t i o n of a h i e r a r c h i c a l o r g a n i z a t i o n developed by Feldman (12). The very long l i s t s are s t o r e d as b i t maps f o r e f f i c i e n t i n t e r s e c t i o n d u r i n g I n q u i r y o p e r a t i o n and s h o r t e r l i s t s are stored i n a compressed format which i s converted to a b i t map f o r i n t e r s e c t i o n . Searching the F i l e . The search programs are divided f u n c t i o n a l l y i n t o two s e c t i o n s : d e f i n i t i o n and e x e c u t i o n . The general philosophy i s that a l l queries are d e f i n e d o n - l i n e through i n t e r a c t i v e programs s p e c i f y i n g search keys, o p t i o n a l i t e r a t i v e q u a l i f i c a t i o n s , and output statements and then s t o r e d . These questions can then be executed e i t h e r o n - l i n e or i n batch mode, w i t h outputs being d i r e c t e d to the t e r m i n a l , to system p r i n t e r s on the mainframe, o r to two types of d i s k f i l e s (RESULTS and SAVE f i l e s ) which can be accessed further by I n q u i r y . Both

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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alphanumeric or s t r u c t u r a l data or a combination of each may be requested f o r output. There are three main modes of I n q u i r y , each a l l o w i n g d i f f e r e n t f u n c t i o n s . Their system name and f u n c t i o n f o l l o w s : GET. This mode allows searches by NSC Number, ranges of NSC Numbers, or by s u p p l i e r code. The NSC Numbers can be input from a t e r m i n a l or c a l l e d from a prestored SAVE f i l e . F u l l S t r u c t u r e Search (FSS). This mode a l l o w s searches by molecular formula w i t h o p t i o n a l q u a l i f i c a t i o n by number of r i n g s , d i r e c t attachments to r i n g , number of dot disconnected fragments, or iterative search, i . e . , atom-by-atom and bond-by-bond. Substructure Search by any combination o f i l e used as a key. Output can be q u a l i f i e d by i t e r a t i v e search. A key l o g i c statement i s r e q u i r e d using some combination of the keys already described. Query D e f i n i t i o n . The d e f i n i t i o n of a question i s a two step procedure. Once the question has been d e f i n e d by the user i n his own mind i n terms of i n f o r m a t i o n a v a i l a b l e i n the system, component p a r t s of the query such as the keys, any individual s t r u c t u r e s needed f o r i t e r a t i v e search, and a l i s t of output data items are input i n t e r a c t i v e l y from a t e r m i n a l , w i t h e d i t programs v a l i d a t i n g each command. Once a component i s input and s t o r e d under a user name i n a f i l e c a l l e d the INQDFTN f i l e , the components are assembled, using whatever l o g i c a l r e l a t i o n s h i p that i s r e q u i r e d , i n t o a f u l l query which i s i t s e l f s t o r e d by name. This query can then be searched o n - l i n e using the t e r m i n a l or run l a t e r , using a batch v e r s i o n of I n q u i r y . An example of the prestored component pieces of an SSS query for Nucleosides and the r e s u l t i n g query i s shown i n F i g u r e 5. The individual keys, structure and Data Item l i s t and their i d e n t i f y i n g names are shown as w e l l as an example of the l a t e r prompting i n which the l o g i c a l r e l a t i o n s h i p of the components i s stored as a question. S t r u c t u r e SI was entered using a v a r i a t i o n of the query prompting language o r i g i n a l l y developed by Feldman (12) but modified and r e w r i t t e n i n PL-1. Short commands b u i l d a connection t a b l e i n core w i t h the corresponding p i c t u r e of the numbered t o p o l o g i c a l framework appearing on the screen. The user can then use t e r s e commands corresponding to the numbered p i c t u r e to i n d i c a t e the l e v e l of s p e c i f i c i t y of each atom, u s i n g a v a r i e t y of s p e c i f i c and generic atom types to q u a l i f y these by data ( i n c l u d i n g hydrogen count, a l l o w a b l e unshown bonding, e t c . ) and to set a bond to any combination of the CAS bond types. The system d e f a u l t s to c e r t a i n bond types on the assumption that i t i s

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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Figure 5.

NUC C5N(2,) MIN RIN C3 N2 RSI 5,6 MIN RIN C4 S BOND A(O) N(O) RIN C4 Ο BOND A(O) N(O)

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DATA

(FIRST SUPPLIER A N D A C T I V I T Y INDICATOR)

S D A T A : FSUP, MCCO

and storage of a substructure search question

E N T E R COMMAND: SSS NUCLEOSIDE K E Y LOGIC: SI K1 K2 K3 (K4 OR K5) I T E R A T I V E S E A R C H (Y/N): Y S T R U C T U R E LOGIC: S1 D A T A ITEM LIST: S D A T A C H E M CARDS? ( Υ / Ν ) : Ν S A V E FILE? (Y/N/*): Y FILE S A V E 8 ASSIGNED E N T E R TERMINATION: E N D SSS C O M M A N D C O M P L E T E D

O R G A N I Z A T I O N OF COMPONENTS IN S E A R C H

K1: K2: K3: K4: K5:

PRESTORED SEARCH COMPONENTS KEYS

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p r e f e r a b l e t o r e t r i e v e f a l s e responses than t o l o s e v a l i d ones, although these d e f a u l t s can be o v e r r i d d e n . Thus i f a user specifies a r i n g double bond, the system w i l l a l s o a l l o w tautomeric, a l t e r n a t i n g and d e l o c a l i z e d bonds. Since the bonds i n the example are set as " r i n g don't c a r e " , any r i n g bonds w i l l be retrieved, including ring single. The keys named K l through K5 shown i n F i g u r e 5 are a l l designed t o r e t r i e v e r i n g keys a p p r o p r i a t e t o the s u b s t r u c t u r e desired. Ring keys a r e not assigned a u t o m a t i c a l l y from an i t e r a t i v e s t r u c t u r e but i n s t e a d a r e entered i n a shorthand n o t a t i o n t h a t a l l o w s user c o n t r o l over the degree of s p e c i f i c i t y i n the key. Thus, key K l w i l l access any NUC Keys w i t h f i v e carbons (C5), two or more Nitrogens (N(2,)) p l u s any other elements (MIN), w i t h any type of bonding allowed. K3 w i l l r e t r i e v e any 5,6 r i n g r e g a r d l e s s of f u s i o n . While K4 and K5 s p e c i f y exact r i n g formula unsaturated bonds (BON The Data Item l i s t SDATA shown i n F i g u r e 5 s p e c i f i e s that data types FSUP ( o r i g i n a l s u p p l i e r code), and MCCO ( b i o l o g y a c t i v i t y i n d i c a t o r ) should be r e t r i e v e d and p r i n t e d w i t h every answer. O r g a n i z a t i o n of the Query. Once the components are s t o r e d , a user invokes the f o r m u l a t i o n prompter f o r SSS and puts together l o g i c a l r e l a t i o n s h i p of components u s i n g the names s t o r e d i n INQDFTN. The program i n t e r a c t i v e l y checks the l o g i c f o r syntax, and determines i f the components are a c t u a l l y i n the INQDFTN f i l e and are a p p r o p r i a t e f o r the p a r t i c u l a r type of search being s e t up. As can be seen i n F i g u r e 5, the keys are put i n t o a boolean expression ("AND" l o g i c i s the d e f a u l t ) and the s t r u c t u r e SI i s i n c l u d e d t o a l l o w generation of augmented atoms a t execution time. SI i s a l s o the atom by atom expression that w i l l be used t o q u a l i f y the key h i t s . The data item l i s t s DATA s p e c i f i e s the two alphanumeric data items that w i l l be r e t r i e v e d and p r i n t e d i f present on the f i l e . A SAVE f i l e was s p e c i f i e d here t o permanently s t o r e the NSC Numbers or answers to the query i n case f u r t h e r manipulation i s necessary. The query i s s t o r e d under the name "NUCLEOSIDE" f o r l a t e r access. I n q u i r y Execution. Search execution may be done completely i n t e r a c t i v e l y , completely i n batch, or p a r t l y i n t e r a c t i v e l y w i t h completion i n batch. A l l modes of search have a r e q u i r e d key search i n which the a p p r o p r i a t e search index i s accessed, t h e requested NSC numbers a r e r e t r i e v e d , f o l l o w e d by an o p t i o n a l i t e r a t i v e search. I n GET, t h i s key search i n v o l v e s a simple lookup of the d e s i r e d NSC numbers. I n FSS the h i e r a r c h i c a l extended molecular formula (EMF) index i s scanned f o r p a r t i c u l a r moleforms p l u s any r i n g , attachments, and number of fragments s p e c i f i e d . I n SSS the key expression i s analyzed and expanded

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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RiCHMAN E T A L .

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from t h e shorthand n o t a t i o n used, the a p p r o p r i a t e i n v e r t e d l i s t s accessed, i n t e r s e c t e d and a r e s u l t a n t l i s t formed f o r f u r t h e r qualification. The i n t e r a c t i v e execution of the search shown i n F i g u r e 5 would be invoked by the command "SEARCH NUCLEOSIDE". The s t r u c t u r e SI would generate AA keys and a l l p o s s i b l e miscellaneous and element keys. A l l permutations of i n d e f i n i t e elements such as " E l " and "SO" would be generated (although "Ht" f o r a l l hetero atoms, i s too i n d e f i n i t e t o do t h i s ) . These augmented atoms (with any bond a l t e r n a t i v e s i n c l u d e d i n each k e y ) , the r i n g o r i e n t e d keys, and any other keys are processed through the Chemsearch Index t o r e t r i e v e i n d i v i d u a l s p e c i f i c i n v e r t e d l i s t s or bitmaps. These l i s t s a r e then i n t e r s e c t e d according t o t h e l o g i c a l expression given. The program d i s p l a y s the number of key answers. The user has the o p t i o n of c a n c e l l i n g t h e search o r c o n t i n u i n g w i t h e i t h e r fragment o inspected on the t e r m i n a time. The user can end the search a f t e r t h i s i n s p e c t i o n o r c a n c e l p r i n t and route a l l output t o a d i s k f i l e . Output. Based on what i s requested i n Query D e f i n i t i o n , and on what a user commands during I n q u i r y E x e c u t i o n , the output of a search can be d i r e c t e d t o an alphanumeric t e r m i n a l , t o a T e k t r o n i x graphics t e r m i n a l i f s t r u c t u r e s a r e needed, t o CAS system p r i n t e r s , to a transaction f i l e (PTFC) f o r the Communications Processor t o produce standard chemistry cards a t CAS, or t o two types of d i s k f i l e s : a temporary browsing f i l e (RESULTS); o r a permanent SAVE f i l e which can be accessed e i t h e r s e q u e n t i a l l y through GET o r as a search key i n SSS. Other Features. Although the main modes o f I n q u i r y are GET, FSS, and SSS, another f u n c t i o n of I n q u i r y c a l l e d LOGX a l l o w s a u t h o r i z e d I n q u i r y users t o remotely access the l a s t NSC number assigned by the CIS i n i t s batch p r o c e s s i n g of new compounds. One or more new NSC Numbers or new Sample Numbers f o r p r e v i o u s l y - a s s i g n e d NSC Numbers can be reserved t o a l l o w p r i o r i t y numbering of samples f o r compounds of i n t e r e s t so t h a t they can be shipped f o r t e s t i n g before r e g i s t r a t i o n i n the CIS. The system a l s o has a range of housekeeping commands t o show, d e l e t e or modify s t o r e d items i n INQDFTN t o g i v e a i d t o a user v i a "Help" f i l e s and t o provide s e c u r i t y v i a passwords and other p r o t e c t i v e measures. Hardware and Software The DR&D CIS i s run a t CAS on an IBM 370/168 under a v i r t u a l o p e r a t i n g system (MVS). Other hardware used a t CAS t o support NCI s t r u c t u r e input and output needs i n c l u d e : chemical t y p e w r i t e r s , a CAS-developed r e f r e s h e d graphics s t r u c t u r e input system based on a PDP-15 and used i n the On-Line S t r u c t u r e Input System (OLSIS) (15)

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which can be used to show stereochemistry i n s t r u c t u r e s ; and a non-impact o f f - l i n e V a r i a n / S t a t o s p r i n t e r used to produce a l l l a r g e s c a l e s t r u c t u r e output requirements of the system r e s u l t i n g from batch p r o c e s s i n g . As f o r a l l other NCI-developed programs i n the CIS, the I n q u i r y subsystem i s w r i t t e n i n PL-1 and uses approximately 1200K bytes of main memory when run without o v e r l a y s . This memory requirement can be c o n s i d e r a b l y reduced when o v e r l a y i n g i s used; however, I n q u i r y operates best without the use of t h i s segmentation. The telecommunications l i n k i s accomplished through the IBM TCAM i n t e r f a c e and c u r r e n t l y three p o r t s are used to support t e r m i n a l s at NCI i n S i l v e r S p r i n g , Md., at the storage and d i s t r i b u t i o n c o n t r a c t o r i n Bethesda, Md., and at CAS i n Columbus, Ohio. At NCI the equipment used i n c l u d e a H a z e l t i n e 2000 CRT w i t h 120 cps p r i n t e r and tape c a s s e t t e u n i t to handle alphanumeric data and a T e k t r o n i x 4012 w i t h hard copy u n i t f o r v e c t o r graphics s t r u c t u r be switched through a leased f o r e i g n exchange l i n e to Columbus at 1200 baud. I n t e r a c t i o n of the System w i t h Other Data Bases While the DRD CIS was implemented p r i m a r i l y to process compounds acquired f o r antitumor screening and t o permit querying the f i l e s o n - l i n e , the data base has been used f o r a v a r i e t y of drug development needs such as these d e s c r i b e d below. Name Index. Since the DR&D CIS uses the CAS R e g i s t r y techniques, the format of the DTP and CAS R e g i s t r y S t r u c t u r e f i l e s are i d e n t i c a l . (To preserve the c o n f i d e n t i a l i t y of the NCI compounds, however, the two f i l e s are separate and d i f f e r e n t check d i g i t a l g o r i t h m s are employed.) B u i l d i n g on t h i s c h a r a c t e r i s t i c of i d e n t i c a l f i l e formats, the Overlap D e t e c t i o n system was developed to i d e n t i f y substances common to both f i l e s and to maintain a cross r e f e r e n c e of t h e i r CAS R e g i s t r y Numbers t o the DTP IRN and thereby to NSC numbers. On a r e g u l a r schedule, "non-systematic names" i n the CAS master name f i l e are r e t r i e v e d by a l g o r i t h m i c examination and the CAS R e g i s t r y numbers of these names passed a g a i n s t the Overlap F i l e to r e t r i e v e any corresponding NSC numbers. These name records are then merged w i t h a separate NCI nonsystematic name f i l e , s o r t e d by name, and photocomposed to p r i n t the Drug Development (DTP) Name Index. This index i n c l u d e s a l l CAS and NCI "non-systematic names" and molecular formulas w i t h the corresponding CAS R e g i s t r y number and NSC number, whichever of these numbers i s a v a i l a b l e . Thus, given a nonsystematic name, a user of the index may be l e d to an NSC number and thereby to any other data i n the chemical or b i o l o g i c a l data f i l e s . I f there i s no NSC, the CAS r e g i s t r y number can be used to look up the systematic name i n the CAS R e g i s t r y Number Handbook or r e f e r e n c e other p u b l i c a t i o n s w i t h R e g i s t r y number indexes. The CAS R e g i s t r y Numbers are being added to the Cross Reference f i l e of the DR&D

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

13.

RICHMAN

E TAL.

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CIS t o be r e t r i e v e d literature.

Chemical

as needed

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217

System

to f a c i l i t a t e

access

to

the

L i t e r a t u r e Searching. Searches are made of the l i t e r a t u r e t o i d e n t i f y compounds worthy o f a c q u i s i t i o n because of t h e i r r e p o r t e d b i o c h e m i c a l o r other b i o l o g i c a l p r o p e r t i e s or because of t h e i r structural characteristics. Chemical A b s t r a c t s S e r v i c e ' s CASIA (and CA CONDENSATES) f i l e s were searched by p r o f i l e s of DTP i n t e r e s t , e.g., compounds which i n h i b i t DNA or RNA s y n t h e s i s . The output i s a l i s t i n g c o n t a i n i n g the CA a b s t r a c t number, i n d e x i n g terms f o r the a r t i c l e , and f o r each compound i n t h e a r t i c l e i t s CAS R e g i s t r y Number, molecular formula, systematic name, and indexing terms as w e l l as the corresponding NSC Number, i f t h e substance was a l s o r e g i s t e r e d i n the DR&D CIS. (The NSC Number i s obtained by computer match of CAS R e g i s t r y numbers a g a i n s t the cross-reference f i l e o D e t e c t i o n procedures describe f i l e f o r NSC Numbers so r e t r i e v e d provides i n f o r m a t i o n such as the compound's antitumor a c t i v i t y or whether an a d d i t i o n a l supply i s needed t o complete testing. The s t r u c t u r a l diagrams f o r t h e compounds r e t r i e v e d from the ÇA data base are generated by CAS A l g o r i t h m i c S t r u c t u r e D i s p l a y (ASD) program from t h e connection t a b l e i n the CAS R e g i s t r y S t r u c t u r e f i l e . A f t e r reviewing these data and t h e a b s t r a c t (or o r i g i n a l a r t i c l e , i f needed), an a c q u i s i t i o n e f f o r t i s made f o r s e l e c t e d compounds. A s i m i l a r but l e s s automated approach i s used when data bases other than ÇA a r e searched. Substructure searches of ÇA were made w i t h the cooperation of the Basel Information Center f o r Chemistry i n S w i t z e r l a n d . The output i s a l i s t i n g of CAS R e g i s t r y Numbers of compounds which meet the search c r i t e r i a , t h e i r corresponding ÇA a b s t r a c t number and a m i c r o f i l m copy of the corresponding a b s t r a c t . The s t r u c t u r e s of these r e t r i e v e d compounds are input f o r a Search on Topology (SRT) a g a i n s t the DR&D CIS f i l e s t o i d e n t i f y i n t h a t f i l e compounds which are d u p l i c a t e s o r near d u p l i c a t e s . The output of SRT, the a b s t r a c t s (or a r t i c l e s of i n t e r e s t ) and s t r u c t u r e diagrams (generated by the automated A l g o r i t h m i c S t r u c t u r e D i s p l a y procedure) a r e reviewed by DTP t o select compounds f o r acquisition. Substructure searches f o r a c q u i s i t i o n purposes have a l s o been made of other data bases such as the Index Chemicus Registry System maintained by t h e I n s t i t u t e of S c i e n t i f i c Information. 1

P r e s e l e c t i o n Subsystem. The f o l l o w i n g three "stand-alone" c a p a b i l i t i e s are a v a i l a b l e t o a i d m e d i c i n a l chemists i n making the optimal s e l e c t i o n f o r a c q u i s i t i o n from among a v a i l a b l e compounds: the R e g i s t r y ' s Search on Topology (SRT) program which identifies d u p l i c a t e s and near d u p l i c a t e s ; the S p e c i a l S t r u c t u r e Feature I d e n t i f i c a t i o n (SSFID) processor which i d e n t i f i e s analogs of Program i n t e r e s t ; and a s t a t i s t i c a l model (20) which calculates

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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the p r o b a b i l i t y of antitumor a c t i v i t y of a compound based on an a n a l y s i s of i t s chemical fragments and antitumor a c t i v i t y i n the P388 lymphocytic leukemia screen. These three c a p a b i l i t i e s a r e being improved and i n t e g r a t e d i n t o a p r e s e l e c t i o n subsystem t o optimize a c q u i s i t i o n s . A f t e r p r o c e s s i n g p o t e n t i a l a c q u i s i t i o n s through SRT, search keys would be assigned t o the compounds and the data processed by the SSFID processor which w i l l be m o d i f i e d t o i n c r e a s e i t s efficiency. The SSFID processor w i l l determine whether p o t e n t i a l a c q u i s i t i o n s are i n : chemical c l a s s e s t o be deemphasized because they a r e l a r g e l y negative or adequately s t u d i e d ; newly-emerging a c t i v e c l a s s e s ; a c t i v e c l a s s e s f o r which a d d i t i o n a l compounds a r e d e s i r e d ; o r c l a s s e s hypothesized t o y i e l d a c t i v e agents. The p r o b a b i l i t y - b a s e d model, as i n other p r e d i c t i v e methods, uses a s e t of known a c t i v e and i n a c t i v e compounds as a t r a i n i n g set t o d e r i v e a weight f o for each s t r u c t u r a l f e a t u r assignment. Since the weight of each f e a t u r e i s based on s t a t i s t i c a l s i g n i f i c a n c e , the a c t i v i t y score f o r a p o t e n t i a l a c q u i s i t i o n i s determined by summing the r e s p e c t i v e weights of t h e structure features. A measure of r a r i t y or uniqueness of s t r u c t u r a l fragment present i n candidate a c q u i s i t i o n s i s a l s o derived. The current model, being used w i t h encouraging r e s u l t s i n an experimental mode, was based on a t r a i n i n g s e t of 2,716 a c t i v e compounds and 15,524 i n a c t i v e s . Work i s ongoing t o evaluate t h e b e n e f i t s of u s i n g a d d i t i o n a l or a l t e r n a t e chemical f e a t u r e s , such as R e g i s t r y I I I Ring ID numbers or g a n g l i a augmented atoms (GAA) which i n c l u d e i n f o r m a t i o n on t h e bonds extending from the t e r m i n a l atoms. I n t e r l i n k between the Chemical and B i o l o g i c a l Systems The t r a n s f e r of machine-processable data from the DR&D CIS t o BDPS r e g a r d i n g a c c e s s i o n s , shipments, and replenishment a c t i o n s has been a l l u d e d t o e a r l i e r . The data t r a n s f e r r e d i n c l u d e s : names and addresses of s u p p l i e r s , s c r e e n e r s , and t h e DTP s t a f f which i s used by the BDPS t o m a i l the summarized b i o l o g i c a l t e s t results; NSC Numbers assigned t o new accessions and other substance-related data such as chemical c l a s s which i s used t o b u i l d the BDPS master c o n t r o l record t o a n t i c i p a t e t e s t data and to r e p o r t the reason f o r a c q u i s i t i o n and s p e c i a l t e s t i n g ; and out of stock and replenishment a c t i o n s which a r e reported t o DTP d e c i s i o n makers. F u r t h e r , NSC Numbers r e t r i e v e d by I n q u i r y from the DR&D CIS may be w r i t t e n onto a c a s s e t t e u n i t which i s p a r t of the Hazeltine terminal c o n f i g u r a t i o n and transformed into t r a n s a c t i o n s f o r querying the BDPS t o r e t r i e v e t h e t e s t r e s u l t s for these substances. However, there i s no t r a n f e r of evaluated t e s t r e s u l t s or other data from the BDPS t o the DR&D CIS. I t should be noted t h a t the DR&D CIS data base i s r e s i d e n t i n Columbus, Ohio and i s queried i n an o n - l i n e i n t e r a c t i v e mode,

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

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RiCHMAN E T A L .

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w h i l e the BDPS i s r e s i d e n t i n Bethesda, Maryland i n NIH's D i v i s i o n of Computer Research and Technology, and i t ' s s e r i a l tape f i l e s queried i n batch. There i s as yet no c a p a b i l i t y of producing a r e p o r t combining s e l e c t e d data from both data bases l e t alone browse i n both data bases, r e g a r d l e s s o f the system i n which t h e query o r i g i n a t e d . The f a c t that we have r e c e n t l y generated s t r u c t u r e s by ASD f o r the b u l k of the 227,000 compounds r e g i s t e r e d before the s t a r t of the DR&D CIS i s a s i g n i f i c e n t step i n i n t e r f a c i n g these systems more f e a s i b l e . However, new hardware, software and communications are r e q u i r e d before the chemical and biological data bases may be i n t e r f a c e d w i t h improved effectiveness. Acknowledgements S p e c i a l mention i Margaret M i l n e , and Rut for t h e i r e f f o r t s i n the design and implementation o f t h e DR&D CIS; Warren S. Hoffman and h i s team of programmers of E . I . du Pont De Nemours and Company f o r t h e i r e a r l y programming support; and Gary Kurtenbach and Charles Watson of the Chemical A b s t r a c t s S e r v i c e f o r t h e i r support i n system i n s t a l l a t i o n and o p e r a t i o n .

Abstract This automated system was developed t o monitor t h e a c c e s s i o n , s t o r a g e , and d i s t r i b u t i o n o f chemicals and drugs acquired f o r antitumor t e s t i n g . The system i d e n t i f i e s d u p l i c a t e s and analogs of Program i n t e r e s t , produces a c t i o n and i n f o r m a t i o n a l documents r e q u i r e d by the drug development a c t i v i t y , maintains i n v e n t o r y c o n t r o l , i n t e r f a c e s w i t h the B i o l o g y Data Processing System which e v a l u a t e s and disseminates screening r e s u l t s , and t r a c k s a c q u i s i t i o n s from r e c e i p t through shipment t o the screening l a b o r a t o r i e s and the r e t u r n of the excess supply. An o n - l i n e , i n t e r a c t i v e r e t r i e v a l subsystem permits s u b s t r u c t u r e and f u l l structure searching on a f i l e of 310,000 compounds. R e s u l t s of searching other data bases f o r s t r u c t u r a l m o i e t i e s and b i o l o g i c a l p r o p e r t i e s a r e l i n k e d w i t h the system t o i d e n t i f y compounds worthy of a c q u i s i t i o n . An index of nonsystematic names i n the Chemical A b s t r a c t s r e f e r e n c e d to compounds i n the system i s generated.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

RETRIEVAL OF MEDICINAL CHEMICAL INFORMATION

220 Literature

Cited

1. Zubrod, C . G . , Schepartz, S., L e i t e r , J., Endicott, K.M., Carrese, L.M., Baker, C.G., "The Chemotherapy Program of the N a t i o n a l Cancer Institute: H i s t o r y , A n a l y s i s , and P l a n s , " Can Chem. R e p . , (1966), 50, 349-540. 2. I h n d r i s , R . W . , "Chemical S t r u c t u r e Fragmentation for Use i n a Coordinate Index R e t r i e v a l System," J. Chem. Doc., (1964), 4, 274-278. 3.

Leiter, D.P., Morgan, H.L., Stobaugh, R.E., "Installation and Operation of a R e g i s t r y for Chemical Compounds," J. Chem. D o c . , (1965), 5, 238-242.

4. Morgan, H.L., "The Generatio f o r Chemical S t r u c t u r e A b s t r a c t s S e r v i c e , " J. Chem. Doc., (1965),

5,

103-113.

5. Hazard, G.F.Jr., Murray, B . R . , "The Use of the Chemical A b s t r a c t s R e g i s t r y System in a Drug Development Program," 7th Annual M i d d l e A t l a n t i c Regional Meeting of the American Chemical S o c i e t y , P h i l a d e l p h i a , P a . , 1972. 6. Hazard, G.F.Jr., "The Use of the CAS Substructure Search System on a Large Drug Development Chemical File," presented at the 162nd Meeting of the American Chemical S o c i e t y , September, 1971. 7. Wigington, R . L , "Machine Methods for Accessing Chemical Abstracts Service I n f o r m a t i o n , " 97-120, i n "Proceedings of IBM Symposium on Computers and C h e m i s t r y , " IBM DATA Processing Division, White Plains, New York, 1969. 8.

First and Second Updates to the CAS Facility for Integrated Data O r g a n i z a t i o n , Users Manual, 1974 NTIS PB 242-856

9. Ditmar, P.G., Stobaugh, R . E . , Watson, C.E., "The Chemical Abstracts Service Chemical R e g i s t r y System. I. General D e s i g n , " J. Chem I n f o . Comput. Sci., (1976), 16, 111-121 10. F r e e l a n d , R . G . , Funk, S.J., O'Korn, L.J., Wilson, G.A., "Augmented C o n n e c t i v i t y Molform - A Technique for R e c o g n i t i o n of S t r u c t u r e Topology I d e n t i t y , " presented at the 169th National Meeting of the American Chemical Society, P h i l a d e l p h i a , P a . , April, 1975. 11. Blackwood, J.E., Elliott, P.M., Stobaugh, R.E., Watson, C.E., "The Chemical A b s t r a c t s Service Chemical R e g i s t r y System. III S t e r e o - c h e m i s t r y , " J . Chem. I n f o . Comput. Sci. (1977), 17,3-8

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221

12. Feldmann, R.J., Heller, S . R . , "An A p p l i c a t i o n of Interactive Graphics-The Nested R e t r i e v a l of Chemical S t r u c t u r e s , " J. Chem. Doc., (1972), 12, 48, 48. 13. Powers, R.V., Hill, H.N., "Designing CIDS - The U . S . Army Chemical Information and Data System," J.Chem. Doc., (1971), 2 1 , 30-38. 14. D i t t m a r , P.G., Mockus, J , Courvreur, K . M . , "An A l g o r i t h m i c Computer Graphics Program for Generating Chemical S t r u c t u r e Diagrams," J. Chem. I n f o . Comput. Sci., (1977), 17, 186-192. 15. B l a k e , J.E., Farmer, N.A., Haines, R . C . , "An I n t e r a c t i v e Computer Graphics System for P r o c e s s i n g Chemical S t r u c t u r e Diagrams," J. Chem. I n f o 16.

Milne, Hazard, G.F.Jr., "A Systematic Analysis of Substructure Search Questions for the Chemotherapy Program of the N a t i o n a l Cancer Institute, 164th N a t i o n a l Meeting of the American Chemical S o c i e t y , August, 1972.

17. "Substructure Search System Documentation," Chemical S e r v i c e , Columbus, Ohio, 1970. 18. Adamson, G.W., Lynch, M.F., Town, W . G . , J. Chem. 1971.

Abstracts

Soc-C,

3702,

19. Milne, Μ., Hazard, G.F.Jr., " N a t i o n a l Cancer I n s t i t u t e Drug Research and Development Chemical Information System: Substructure Search," 169th N a t i o n a l Meeting of the American Chemical S o c i e t y , April, 1975. 20. Hodes, L., Hazard, G.F.Jr., Geran, R.I., Richman, S., "A Statistical-Heuristic Method for Automated S e l e c t i o n of Drugs for S c r e e n i n g , " J. Med. Chem., (1977), 20, 469-475. RECEIVED August 29, 1978.

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

INDEX A

AA (augmented atom) Abbott Automated Biological and Chemical Data System (ABCD) ABCD (Abbott Automated Biological and Chemical Data System) Accession index file ACCIS (see Agricultural Chemicals Computerized Information System ) Agricultural Chemicals Computerized Information System (ACCIS) ... design criteria flow of information into report, typical search capabilities system organization Agricultural research Algorithmic Structure Display ( ASD ) Antitumor activity of a compound .... ASD (Algorithmic Structure Display) Atoms nature of attachment between relationships among the special types of special Augmented atom ( AA ) Author index Automated data entry Automation of data processing data recording information transfer test-data transmission from pro ducer to computer master file ..

209 20 20 182

168 168 170 171 172 169 20 217 218 217 192 187 187 209 14 23 29 29 31

Biological (continued) data (continued) Processing System (BDPS) 203 principal files of 204 retrieval system for drug devel opment, integrated chemi cal and 181 sheet 87,88 Company, on-line chemical and 107 search (es) 174 combinations, uses of chemical and 179 integrated system for conducting chemical and 168 system 174 systems, interlink between chemi cal and 218 Biology file 134 retrieval subsystem 184,191 subsystem 195 search 197 Blinking-arrow option 116 molecule development by 117 BN (sample number) 184 Bond-character modification 112 Bond, unspecified 187 Boolean expression 214 logic 176 operators 191

20 C

Β Basel Information Center for Chemistry 217 Batch mode 174 Batch system, card-oriented 176 BDPS {see Biological Data Processing System) Biodata systems structure 85 Biological and chemical data files interaction 103 and chemical data interaction 105 data 5,85 integration of 128 at Merck & Co., Inc., use of 85

Candidate-selection process 128,129 Card-oriented batch system 176 CAS ( see Chemical Abstracts Service ) Cc (chain carbons) 187 Chain carbons (Cc) 187 Chain growth for a molecule 116 Chemdata enhancements 100 searches' statistics during 1977 104 systems at MSDRL 95 Chemical(s) Abstracts Service (CAS) 132 files 134 at WL/PD 136

223 In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

224

RETRIEVAL

Chemical ( s ) ( continued ) Abstracts Service (continued) future developments at 141 Registry files 136 III Integrated Information System Warner-Lambert/ Parke-Davis132 Number 58,147 System 132 III System, NCI version of 203 SUBSS 176 system flow 178 having an aromatic ring, NIOSH TTECS data base for 158 and biological data retrieval system for drug development, integrated 181 inforamtion system at the Upjohn Company, on-line 10 search combinations, uses o searches, integrated system for conducting 168 systems, interlink between 218 data 5, 95 files 93 interaction, biological and 103 interaction, biological and 105 at Merck & Co., Inc., use of 85 system 86 descriptors 58 dictionary file on-line (CHEMLINE) 58,59 abbreviations 60 -RTECS substructure search 68, 71 for chlorinated dibenzodioxins 68 substructure search (es) 65 approach 66 - T O X L I N E search 63, 64 unit record 59 and drug accessioning and screening activities, interaction of DTFs 202 Information Data Systems (CIDS) 150 key(s) 150,153 search for all cyclohexyl (SCH49) morpholine (SCN35) compounds 154 structure keys, Edgewood 147 Informational Retrieval System (CIRS) 198 applications of 198 WRAIR 181 Information System (CIS) 144,145,200 with accessioning and screening, interaction of 201 areas of 144 data bases being added to 148

O F MEDICINAL

CHEMICAL

INFORMATION

Chemical(s) (continued) Information System ( continued ) drug research and development 200 evolution of 200 medicinal 1 NIH/EPA 144 Unified data base (UDB) 144,146 Name File 97, 99 retrieval subsystem 182, 185 sample inventory system 100 structure hyperspace 54 Information System (CSIS) 95, 144 search commands 102 system 97, 99 record 97,98 search key to biological information 58 searching 107,108 subsystem 185, 193 search 197 Chemistry, Basel Information Center for 217 CHEMLINE (see CHEMical dictionary file on-LINE ) Chemsearch index file 211 Chlorinated dibenzodioxins, CHEMLINE-RTECS substructure search for 68 CIDS (see Chemical Information Data Systems ) CIRS (see Chemical Information Retrieval System ) CIS (see Chemical Information System ) Clustering in free-text data bases 39 Code sheet 22 Code word index 14 Columns, free-form 87 COM (Computer Output Microfilm) 90, 92 Compatibility with existing computer systems 24 Complete Structure Search (IDENT) Identity 161 Complications, additional 90 Compound antitumor activity of a 218 registry and search system 118 repository record 97, 101 Computer files, combining of different 138 graphics system 176 masterfile,automation of test-data transmission from producer to 20 master file, data conversion from producer to 28

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

225

INDEX

Computer (continued) output microfilm (COM) 90,92 storage, outline of data record for . 86 system, stand-alone 109 systems, compatibility with existing 24 Connection tables 184,186 Control options 113 Cost-effective testing programs 90 Cross indexing 182 Cross-reference file, NSC 203 CSIS (see Chemical Substance Information System) Cumulative distributions 48 with normal frequency distribution 49 Cumulative frequency distributions .. 49 Cuts 53 Cyclohexyl (SCN49) morpholine (SCN35) compounds, CIDS key search for all 154

Data (continued) file(s) (continued) interaction, biological and chemical medical use function requirements, medicinal chemistry independence information system, automated diuretic integration of biological interaction, biological and chemical management/distribution at Merck & Co., Inc., use of chemical and biological multiple-use table summary nonstructural pharmacology quality of

D Data analyzer 93, 94 base(s) being added to the CIS 148 for chemicals having an aromatic ring, NIOSH TTECS 158 clustering free-text 39 fragments 136 GDS ( graphical data structure ) .. 136 IMS 175 INQUIRE (Infodata Systems Inc.) 10,133 management system 10,133 system 136 interfaces, SANSS164 names 136 PRODBIB 10 content 13 structure 108 substance 136 text 53 transaction file 100 utilization of 19 biological 5, 85 chemical 5 conversion 27 from producer to computer master file 28 diuretic 31 entry 19 automated 23 manual 20 system, Entrex 137 terminal 109,110 exact-structure 123 file(s) chemical 93 diuretic 34

of 86 retrieval system for drug development, integrated chemical and biological 181 secondary 8 sheet, biological 87,88 standardization, purpose of 32 substructure 123 systems, outline of chemical and biological 86 types required for medicinal chemistry 6 use-oriented 44 DEC-System 10, R & D 29 Declassification decision 208 Descriptors, chemical 58 Descriptors (use types) 53 Developmental Therapeutics Program (DTP) 200 chemical and drug accessioning and screening activities, interaction of 202 Name Index 216 NCFs 200 selected system outputs 206 DISPLAY command 122 options 149 structure 122 Distribution table 46 Diuretic data 31 file 34 information system, automated 33 Document file 134 Dominant use pairs 45 DR & D CIS (see Drug Research and Development Chemical Information System) DRAW option 116

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

103 40 3 123 33 128 105 7 85 43 123 31 3

RETRIEVAL

226

Drug accessioning and screening activi ties, interaction of DTP's chemical and 202 development integrated chemical and biologi cal data retrieval system for 181 process 2 functions 3 hypothetical 4 information needs related to the 3 name with field value condition 16 name plus key word 15 record sheets 30 research and development Chemical Information System (DR & D CIS) 200,201 design constraints of 201 evolution of 20 files, growth rate of 20 files, size of 206 hardware 215 as nodes in an interconnected network 207 software 215 system as a network of processors 205 DTP ( see Developmental Thera peutics Program ) Ε

Edgewood CIDS structure keys 147 E L E (element keys) 211 Element keys (ELE) 211 Ε MF (extended molecular formula) 211,214 Encoding searches problems 176 End-user orientation 8 Environmental Protection Agency (EPA) 144 Toxic Substances Control Act (TSCA) Inventory Candidate List 58 EPA (see Environmental Protection Agency ) Error checks 35 Exact-structure data 123 Expert language 121 Extended molecular formula (EMF) 211,214 F

Field value condition, drug name with Fields definition table File(s) 1 chemical name

16 12 123 97

O F MEDICINAL

CHEMICAL

INFORMATION

File(s) (continued) miscellaneous 91 protocol 87 structure 203 Flexibility 24 FLIP option 113 Format, SS minicomputer storage 127 Format, transaction file record 101 FPROBE (Fragment Search) 158,162 Fragment -based systems 108 -coded search system 108 data base 136 relationships 191 search (FPROBE) 158,162 Fragmented compounds 119 Free -form columns 87 -form parameters 91 distribution cumulative functions, nature of token values sort for uses per compound FSS (Full-Structure Search) Full-Structure Search (FSS)

46 49 48 51 47 212 212

G GDS ( graphical data structure ) data base Geneva system of nomenclature GET GLP ( good laboratory practice ) guidelines Good laboratory practice (GLP) guidelines Graphical data structure (GDS) data base entry system display structure input

136 39 212 24 24 136 112 Ill

H Hardware 25, 109 configuration 137 DR & D CIS 215 portability 23 Herbicide current awareness report .. 171 High mean uses per compounds 53 Hyperspace, chemical structure 54 I IDENT (Identity) Complete Struc ture Search Image Systems, Inc

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

161 133

227

INDEX

IMS data base 175 IND, Investigation New Drug application 2 Infodata Systems Inc. data base management system (INQUIRE) 10,133,136 file(s) 133 format 135 Information into ACCIS, flow of 170 future trends in medicinal chemical 8 groups, in-house 8 needs related to the drug develop ment process 3 retrieval, purpose of medicinal chemical 3 system(s) automated diuretic data 33 Chemical Structure (CSIS) 95 medicinal chemical 1 at the Upjohn Comany, on-line chemical and biological 107 Warner-Lambert/Parke-DavisCAS Registry III Integrated 132 transfer, automation of 31 Index author 14 code word 14 (DTP) name 216 file accession 182 Chemsearch 211 screen 183 Merck 39 name 216 policy 11 In-house information groups 8 INQUIRE (see Infodata Systems Inc. data base management system) INQUIRY execution 214 other features of 215 subsystem 205,208,209 three main modes of 212 Integrated chemical and biological data re trieval system for drug development 181 Information System, WarnerLambert/Parke-Davis-CAS Registry III 132 system for conducting chemical and biological searches 168 Integration 8 INTER command 162 Interaction of the CIS with accessioning and screening 201

Interaction ( continued ) of the DRD CIS system with other data bases 216 of DTP's chemical and drug acces sioning and screening activities 202 Interagency Regulatory Liaison Group (IRLG) 147 Internal structure representation Ill Inventory retrieval subsystem 185,191 subsystem 195 search 197 system, chemical sample 100 system, net 104 Investigation new drug application (IND) 2 IRLG (Interagency Regulatory Liaison Group) 147 v

Journeys

208 Κ

Key -to-disk entries word drug name plus list prefixed

134 15 19 14

L L-number Lab I.D. (laboratory identification number) Laboratory identification number (Lab I.D.) Language expert novice user Lead structure types Listings Literature searching "Locator" designation Log-normal distribution Low mean uses per compound LSD, nomenclature search for

85 184 184 121 121 121 2 17 216 58 48, 53 53 152

M

MALIMET terms Management/distribution data Manual data entry ... Master file, data conversion from producer to computer Mean uses per compound high and low v

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

15 7 20 28 53 53

RETRIEVAL

228

Medical use data file 40 Medical uses in the Merck Index, qualifiers given to 41 Medicinal chemical information current status 5 future trends 8 organization status 5 retrieval 1 purpose of 3 systems 1 Medicinal chemistry 1 data function requirements 3 data types required for 6 major data types required for 5 Merck & Co., Inc., use of chemical and biological data at 85 Index 39 qualifiers given to medical uses in 41 Sharp and Dohme Research tories (MSDRL) 8 Chemdata Systems at 95 MF (see Molecular Formula Search) Minicomputer, SS 126 storage format 127 M ISC (miscellaneous keys) 211 Miscellaneous keys (MISC) 211 Modular search system 173 Modules, functions of 32 Molecular formula, extended (EMF) 211 Formula Search (MF) 155,156 for compounds with 1-4 chlorine atoms 157 Weight Search (MW) 155 Molecule, chain growth for a 116 Molecule development by blinkingarrow option 117 MOVE option 115 MSDRL (see Merck Sharp and Dohme Research Laboratories) Multifile option 136 Multiple-use table summary data 43 MW (Molecular Weight Search) 155 Ν

Name index (DPT) Names data base National Cancer Institute (NCI) Developmental Therapeutics Program version of the CAS Registry III System National Library of Medicine ( N L M ) NCI ( see National Cancer Institute ) NDA (new drug application) Net inventory system

216 136 200 200 203 58 3 103 104

O F MEDICINAL

CHEMICAL

INFORMATION

New drug application (NDA) 3 NI Η/EPA Chemical Information System 144 NIOSH RTECS file 158 NIOSH TTECS data base for chemi cals having an aromatic ring 158 NLM (National Library of Medi cine) 58 Nomenclature Geneva system of 39 Search (NPROBE) 149,151 for LSD 152 Nonstructural data 123 Normal frequency distribution, cumu lative distributions with 49 Novice language 121 NPROBE (see Nomenclature Search) NSC assignment 208 decision 208 NUC (nucleus keys) 209 Nucleosides, example of the prestored component pieces of an SSS query for 213 Nucleus keys (NUC) 209 Ο

Occurrences, use tokens 53 OLSIS (On-Line Structure Input System) 215 On-line chemical and biological informa tion system at the Upjohn Company 107 chemical dictionaryfile(see CHEMical dictionary file on-LINE) CHEMLINE retrieval of TOXLINE 62 Structure Input System (OLSIS) .. 215 substructure search 194 system searches 193 Operators, Boolean 191 Operation programs 90 for particular searches 91 OUTPUT 215 option 116 Overlap Detection System 216 Ρ Paper copy shipment Parke-Davis Research Laboratories Warner-Lambert (WL/PD) CAS Registry III Integrated Information System

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

21 132 132 132

INDEX

229

Pharmacology data 31 PLOT command 123 PLOT structure Format 4 123 Potential benefits 23 Prefixed key words 14 Preselection subsystem 217 Prestored component pieces of an SSS query for nucleosides, example of the 213 Primary software 24 Processor(s) 205 work stations, NSC assignment 208 PRODBIB data base 10 content 13 PRODBIB file, organization of 11 Product information from the published literature, retrieval of 10 Product papers 10 Properties file 133 Protocol file 8 term index to the 8

Retrieval capabilities, substructure 97, 98 criteria 185 options 149 subsystem biology 184,191 chemical 185 inventory 185,191 Ring(s) carbons (Rc) 187 keys (RIN) 211 -linking operation 115, 117 option 113, 114 Search (RPROBE) 158-160 System keys 209 RPROBE (RING Search) 158-160 RSI (RSIZE) key 211 RSIZE (RSI) key 211 RTECS (see Registry of Toxic Effects

S

Q

Sample number (BN) Qualifiers 54 SANSS (see Structure and Nomengiven to medical uses in the Merck clature Search System) Index 41 Screen index file subsets of use tokens 55 Screening Query (ies) 186 activities, interaction of DTP's chemical and drug accessioning atoms 186 and definition 212 data, review of facility 121 Information Center organization 214 interaction of the CIS with structure 186, 188 accessioning and laboratories R monitoring of Rc ( ring carbons ) 187 Search (es) R & D DEC-System 10 29 biological DRBMS (relational data base manbiology subsystem agement system) 123 capabilities, ACCIS Record(s) chemistry subsystem acquisition 87 command ( s ) compound repository 101 CSIS format, transaction file 101 compounds sheets, drug 30 where structure > F l Registry where structure > F2 facility 118 where structure = SI components 119 elements function 118 file organization Number, CAS 147 full-structure (FSS) of Toxic Effects of Chemical inventory subsystem Substances (RTECS) 63 keys, development of file assessment 71 on-line substructure Relational data base management on-line system system (RDBMS) 123 operation programs for particular Report generation 136 parameters Report generator 197 products, typical results file Research proposals, analysis of 198

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

184 183

202 198 169 201 203 198 174 197 172 197 122 102 122 122 121 123 211 212 197 209 194 193 91 98 19 121

230

RETRIEVAL

Search ( es ) ( continued ) strategies 89,196 substructure 198 of CA 217 subsystem 123 system biological 174 fragment-coded 108 modular 173 three-phase 124 on Topology (SRT) 217 types 90,91 Searching chemical structure 107,108 chemical substructure 107, 108 the file 211 literature 217 procedures 193 substructure (SS) 124 Secondary data 8 software 25 sort parameter 46 Security, system 137 Software DR & D CIS 215 function of 125 primary 24 secondary 25 Special atoms, relationships among 187 atoms, types of 187 structure feature identification (SSFID) processor 217 Specificity 50 SRT (Search on Topology) 217 SS (see substructure search) SSFID (special structure feature identification) processor 217 Stand-alone computer system 109 Structural diagrams for retrieved substances 69 Structure data base 108 -drawing operation 113 entry system 108, 109 generated from SANSS structure generation commands 165 input, graphical Ill keys, Edgewood CIDS 147 and nomenclature search system (SANSS) 144,145,147 data base interfaces 164 structure generation commands, structure generated from 165 representation, internal Ill search (IDENT), complete 161 table 126

O F MEDICINAL

CHEMICAL

INFORMATION

SUBSS (see substructure search system ) Substance data base 136 Substructure data 123 retrieval capabilities 97, 98 search (es) (SS) 124,198,212 of CA 217 C H E M LI NE 65 approach 66 -RTECS 68, 71 minicomputer 126 storage format 127 on-line 194 query for nucleosides, example of prestored component pieces 213 subsystem 123 System (SUBSS) 161, 176 CAS 176 tion of table System configuration design criteria operation organization, ACCIS security support

125 126 24 23 25, 26 169 137 24

Τ

Term index to protocol file 87 Test-data transmission from producer to computer master file, automa tion of 20 Testing programs, cost-effective 90 Text data bases 53 Token distribution functions 46 Token frequency distribution func tions, nature of 48 TOXicology information on-LINE (TOXLINE) 62 on-line retrieval of 62 -TOXBACK 62 TOXLINE (see TOXicology infor mation on-LINE) Three-phase search 124 TRAC 208 Transaction file 97,100,133 data base 100 record format 101 Transaction inventory 100 (TSCA) Inventory Candidate List, Environmental Protection Agency's Toxic Substance Control Act 58 Type distribution functions 46

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

231

INDEX

User acceptance 24 υ User language 121 U-number Ill UDB (Unified data base), CIS 144,146 Unified data base (UDB), CIS 144,146 V Unspecified bond 187 Varian V74 137,140 Upjohn Company, on-line chemical and biological information system at 107 W Use(s) Walter Reed Army Institute of combinations 42 Research (WRAIR) 181 per compound, frequency sort for .. 47 Chemical Information Retrieval -compound parameter 42 System (CIRS) 181 correlations 54 subsystems 181 data file, medical 40 distribution file 46, 47 Warner-Lambert/Parke-Davis (WL/PD) 132 frequencies 53 CAS files at 136 -oriented data 44 CAS Registry III Integrated pairs 44 dominant 4 having significant specificity parameter 52 WL/PD (see Warner-Lambert/ Parke-Davis ) token 40 46 occurrences 53 Word distribution table 205 qualifier subsets of 55 Work stations NSC assignment processor 208 type(s) 40,42 classes of 46 WRAIR (see Walter Reed Army Institute of Research) descriptors 53

In Retrieval of Medicinal Chemical Information; Howe, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.