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Prospective identification of biologically active structures by topomer shape similarity searching.

Abstract：

:The principle of bioisosterism-similarly shaped molecules are more likely to share biological properties than are other molecules-has long helped to guide drug discovery. An algorithmic implementation of this principle, based on shape comparisons of a single rule-generated "topomer" conformation per molecule, had been found to be the descriptor most consistently predictive of similar biological properties, in retrospective studies, and also to be well-suited for searching large (>10(12)) "virtual libraries" of potential reaction products. Therefore a prospective trial of this shape similarity searching method was carried out, with synthesis of 425 compounds and testing of them for inhibition of binding of angiotensin II (A-II). The 63 compounds that were identified by shape searching as most similar to any of four query structures included all of the seven compounds found to be highly active, with none of the other 362 structures being highly active (p < 0.001). Additional consistent relations (p < 0.05) were found, among all 425 compounds, between the degree of shape similarity to the nearest query structure and the frequency of various levels of observed activity. Known "SAR" (rules specifying structural features required for A-II antagonism) were also regenerated within the biological data for the 63 shape similar structures.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Cramer RD,Poss MA,Hermsmeier MA,Caulfield TJ,Kowala MC,Valentine MT

doi

10.1021/jm990159q

keywords:

subject

Has Abstract

pub_date

1999-09-23 00:00:00

pages

3919-33

issue

19

eissn

0022-2623

issn

1520-4804

pii

jm990159q

journal_volume

42

pub_type

杂志文章

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