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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
Retrieval of Medicinal Chemical Information Downloaded from pubs.acs.org by 5.62.154.100 on 08/31/18. For personal use only.
ANN F. PENNELL—ICI Americas, Inc., Wilmington, DE 19897 W. JEFFREY HOWE—The Upjohn Company, Kalamazoo, MI 49001
The following paper ωas written by the organizers of the ACS Symposium on Retrieval of Medicinal Chemical Information and is 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
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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 may occur a t v a r i o u s s t a g e s ) . However, the diagram does i n c l u d e a l l of the major f u n c t i o n s and t h e i r approximate 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
Figure 1.
LEAD SELECTION oMASS SCREENING oLITERATURE
MANAGEMENT
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CLINICAL TRIALS
FDA APPLICATION (IND)
FDA APPLICATION (NDA)
PROCESS DEVELOPMENT
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POST MARKETING MONITORING
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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 r e g u l a t i o n s r e l a t i n g to chemical research and manufacturing. 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
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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 t h i s c o n c e p t u a l i z a t i o n the data types are organized as a network around the chemical compound, which i s i d e n t i f i e d by a unique number ( 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
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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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. The management/distribution p o r t i o n of the m e d i c i n a l chemical i n f o r m a t i o n network contains 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.
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(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 supported f i l e s are becoming an important source of p u b l i c i n f o r m a t i o n . These f i l e s are generated to help i n d u s t r y 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-
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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 automated a n a l y s i s of the r e t r i e v e d data. Elabor a t e s t a t i s t i c a l and h e u r i s t i c a n a l y s i s procedures and s o p h 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.
