Toward general methods of targeted library design: Topomer shape similarity searching with diverse structures as queries

Journal of Medicinal Chemistry

Volumn 43, Issue 9, 2000, Pages 1723-1740

  Andrews, Katherine M ^a   Cramer, Richard D ^a  

^a TRIPOS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NEW DRUG;

ALGORITHM; ARTICLE; DATA BASE; DRUG DESIGN; DRUG STRUCTURE; INFORMATION RETRIEVAL; MEDICAL LITERATURE; TECHNIQUE; VIRTUAL REALITY;

DATABASE MANAGEMENT SYSTEMS; DRUG DESIGN; INDICATORS AND REAGENTS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PEPTIDE LIBRARY; RECEPTORS, DRUG; SOFTWARE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0034035557     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm000003m     Document Type: Article

References (63)

1. Molecular Similarity in Drug Design; Dean, P. M., Ed.; Chapman and Hall: London, 1995. Maggiora, G. M.; Johnson, M. A. Concepts and Applications of Molecular Similarity; John Wiley and Sons: New York, 1990.
2. Molecular Similarity in Drug Design; Dean, P. M., Ed.; Chapman and Hall: London, 1995. Maggiora, G. M.; Johnson, M. A. Concepts and Applications of Molecular Similarity; John Wiley and Sons: New York, 1990.
3. A leading reference is: Charifson, P. S.; Corkery, J. J.; Murcko, M. A.; Walters, W. P. Consensus Scoring: A method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins. J. Med. Chem. 1999, 42, 5100-5109.
4. A leading reference is: Wang, T.; Zhou, J. J. Chem. Inf. Comput. Sci. 1998, 38, 71-77.
5. 7 is a reasonable thresh-old if only compounds physically on hand are to be chosen, any computational limitation to 0.000001 of the actual synthetic candidates seems a serious restriction. The structural variety reported here indicates the benefit of as large a candidate pool as possible.
6. Cramer, R. D.; Clark, R. D.; Patterson, D. E.; Ferguson, A. M. Bioisosterism as a molecular diversity descriptor: steric fields of single topomeric conformers. J. Med. Chem. 1996, 39, 3060-3069.
7. Patterson, D. E.; Cramer, R. D.; Ferguson, A. M.; Clark, R. D.; Weinberger, L. E. Neighborhood behavior: a useful concept for validation of molecular diversity descriptors. J. Med. Chem. 1996, 39, 3049-3059. Other important comparative studies, but considering different descriptors, are the following: (a) Matter, H. Selecting optimally diverse compounds from structure databases: a validation study of two-dimensional and three-dimensional molecular descriptors. J. Med. Chem. 1997, 40, 1219-1229.
8. Patterson, D. E.; Cramer, R. D.; Ferguson, A. M.; Clark, R. D.; Weinberger, L. E. Neighborhood behavior: a useful concept for validation of molecular diversity descriptors. J. Med. Chem. 1996, 39, 3049-3059. Other important comparative studies, but considering different descriptors, are the following: (a) Matter, H. Selecting optimally diverse compounds from structure databases: a validation study of two-dimensional and three-dimensional molecular descriptors. J. Med. Chem. 1997, 40, 1219-1229.
9. (b) Brown, R. D.; Martin, Y. C. Use of structure-activity data to compare structure-based clustering methods and descriptors for use in compound selection. J. Chem. Inf. Comput. Sci. 1996, 36, 572-584.
10. Cramer, R. D.; Poss, M. A.; Hermsmeier, M. A.; Caulfield, T. J.; Kowala, M. C.; Valentine, M. T. Prospective Identification of Biologically Active Structures by Topomer Shape Similarity Searching. J. Med. Chem. 1999, 42, 3919-3933.
11. Hodgkin, E.; Andrews-Cramer, K. Knowledge-based Drug Discovery. Modern Drug Discovery 2000, 3, 55-60.
12. Throughout this article, the term "hit" refers to results of a computer search, not to results of a laboratory assay experiment.
13. Lemmen, C.; Lengauer, T.; Klebe, G. FLEXS: A Method for Fast Flexible Ligand Superposition. J. Med. Chem. 1998, 41, 4502-4520. The FLEXS program is distributed by Tripos, Inc.
14. Cramer, R. D.; Patterson, D. E.; Clark, R. D.; Soltanshahi, F.; Lawless, M. S. Virtual libraries: a new approach to decision making in molecular discovery research. J. Chem. Inf. Comput. Sci. 1998, 6, 1010-1023.
15. Almost exactly as in a CoMFA steric field, except that the field contributions of each individual atom are attenuated as more rotatable bonds separate it from a fragment attachment bond. Cramer, R. D., III.; Patterson, D. E.; Bunce, J. D. Comparative Molecular Field Analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc. 1988, 110, 5959-5967. Moreover, there is nothing about the topomer alignment procedure that requires the final similarity comparison to be steric shape only. Thus an extension of topomer similarity, "feature matching" á la conventional 3D pharmacophoric searching, has yielded excellent results in neighbor validation experiments (per ref 6) and is currently being implemented.
16. This compendium of all commercially offered compounds may be obtained from MDL Information Systems, Inc., 140 Catalina Street, San Leandro, CA 94577.
17. For comparison, this RVL contains more than one million times the cumulative number of structures registered by Chemical Abstracts.
18. In practice, particularly for the diamine library, one or two blocking/deblocking operations are highly desirable.
19. Ash, S. M.; Cline, M. A.; Homer, R. W.; Hurst, T.; Smith, G. B. SYBYL line notation (SLN): A versatile language for chemical structure representation. J. Chem. Inf. Comput. Sci. 1997, 37, 1-9.
20. Because topomeric shape differences are computed over CoMFA steric fields, their units are formally kcal/mol. In practice there are three major factors to consider in interpreting these units. (1) Differences are combined, both per lattice point and per fragment, in root-sum-square Euclidean fashion, not by simple addition. So successive small increases in topomer radius will yield increasingly large structural variations. (2) Replacement of a hydrogen by a methyl group produces a shape difference of 60 topomer units. (3) The search radii that have produced statistically significant increases in the frequency of biological activity are in the range of 90 to 120 topomer units.
21. Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. Predicting receptor-ligand interactions by an incremental construction algorithm. J. Mol. Biol. 1996, 261, 470-489.
22. Rusinko, A., III; Skell, J. M.; Balducci, R.; McGarity, C. M.; Pearlman, R. S. Program available from Tripos, Inc., St. Louis, MO.
23. This strikingly lower likelihood of structures in three-piece libraries to be shape similar to a typical query structure, compared to those in two-piece libraries, seems to have several causes. Probably the most important is the additional shape constraint imposed by the second synthetic process needed to form the second bond. As an example of such a constraint, note that the products of amide bond formation can be shape similar only to queries that fragment into something shape-similar to a carbonyl. Thus an amide bond cannot be used to directly connect two rings and can form a one-atom bridge only when the amine is cyclic (e.g., piperidine), but it can form two-atom bridges between rings in the common situations where one of the bridging atoms is sufficiently shape-similar to carbonyl.
24. However, it will usually not be certain whether an alkyl-to-N bond results from leaving group displacement (halide reagent) or from reductive amination (aldehyde or ketone reagent).
25. Addition of virtual libraries that include a Suzuki coupling step would have helped. Indeed, another benefit of this investigation is to call attention to such missing sequences.
26. In two other cases, there was no "matching" hit so no comparison was possible.
27. The 39 other core-built structures in Figure 2 (Diamines, AminoAcids, Dihalides) for which FLEXS and topomer structures agree might seem to counter this judgment. However, in most of those structures there was so little difference in the attachment bond locations that changes in their weight would be immaterial.
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