Topomer CoMFA: A design methodology for rapid lead optimization

Journal of Medicinal Chemistry

Volumn 46, Issue 3, 2003, Pages 374-388

  Cramer, Richard D ^a  

^a TRIPOS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE RECEPTOR STIMULATING AGENT; ANTIVIRUS AGENT; BLOOD CLOTTING FACTOR 10A INHIBITOR; CHOLINESTERASE INHIBITOR; DOPAMINE RECEPTOR BLOCKING AGENT; INTERLEUKIN 1BETA CONVERTING ENZYME INHIBITOR; MONOAMINE OXIDASE INHIBITOR; PROTEINASE INHIBITOR; THROMBIN INHIBITOR; TRYPSIN INHIBITOR;

ARTICLE; CHEMICAL BOND; DRUG CONFORMATION; DRUG POTENCY; METHODOLOGY; STEREOSPECIFICITY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ADENOSINE; COUMARINS; DOPAMINE ANTAGONISTS; ENZYME INHIBITORS; FLAVONOIDS; INDOLES; MODELS, MOLECULAR; OLIGOPEPTIDES; PHENYLALANINE; PIPERAZINES; PYRIDAZINES; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RECEPTORS, CANNABINOID; RECEPTORS, DRUG; RECEPTORS, GABA-A; RECEPTORS, PURINERGIC P1; SULFONAMIDES;

EID: 0037472770     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020194o     Document Type: Article

References (34)

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3. According to one fairly recent publication, "In the papers cited in SCI from 1989 to Dec. 7, 2000, the total number of papers with the keyword "CoMFA" are more than 5000.". Zhu, L. L.; Hou, T. J.; Chen, L. R.; Xu, X. J. 3D QSAR Analyses of Novel Tyrosine Kinase Inhibitors Based on Pharmacophore Alignment, J. Chem. Inf. Comput. Sci. 2001, 41, 1032-1040.
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15. Other approaches exist that do promise direct 3D database searching with potency predictions, such as pseudo-receptor modeling, the Catalyst suite, and post-3D-searching CoMFA. However, these are limited in speed, in range of applicability, and in the number of supporting examples.
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17. A referee notes that CoMFA alignment by the overlap of common cores was independently advocated by Robert S. Pearlman, in connection with the combinatorial library 3D building program Combilibmaker. This approach would of course be applicable only to Case 1 data sets. Similar advice had also been given much earlier by the current author (Cramer, R. D., DePriest, S. A., Patterson, D. E., Hecht, P. The Developing Practice of Comparative Molecular Field Analysis. In 3D-QSAR. H. Kubinyi, Ed.; ESCOM: Leiden, 1993). However none of this previous advice on CoMFA alignments has been systematically evaluated.
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31. The possible inversion of chiral atoms and the neglect of known stereoisomers, in the context of a shape similarity descriptor, need additional explanation. Every potentially chiral atom must in a 3D model necessarily possess an absolute but completely arbitrary (unless externally specified or energetically determined) chirality. Similar structures will have similar shapes only if these arbitrary chiralities are geometrically standardized by appropriate inversions. However, to avoid producing nonsensical ring geometries, the topomer protocol allows only acyclic chiral atoms to be inverted. Quite recently a protocol has been introduced for topomerically standardizing ring pucker as well, by choosing between the two equivalent reflections of such ring geometries. Why then are known stereoforms ignored? Whether a fragment structure is part of a query of a candidate fragment, because the far more numerous unassigned stereoforms will always have been standardized topomerically, any known stereocenter has a roughly 50% chance of being the nontopomeric stereoisomer. As a result, structurally identical fragments would be topomerically dissimilar and unrecognized 50% of the time. Faced with this very unattractive alternative outcome, it was agreed that known stereocenters would be structurally registered but ignored in topomer modeling. Racemic synthons thus become two distinct registered "substances" mapping to the same topomer.
32. One such "quasi-Free -Wilson" QSAR may have been observed among other topomer CoMFA applications. There also appears to be a good diagnostic for such an artifactual correlation, a variance among the predicted or "test set" potencies that is much smaller than the variance of the "training set potencies" used to construct the QSAR model.
33. Clark, M.; Cramer, R. D. The Probability of Chance Correlation Using Partial Least Squares (PLS). Quant. Struct.-Act. Relat. 1993, 12, 137-145.
34. All new technologies described are the subjects ofinternational patent filings.