Prospective identification of biologically active structures by topomer shape similarity searching
Prospective identification of biologically active structures by topomer shape similarity searching
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DOI：
10.1021/jm990159q
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发表时间：
1999-09-23
影响因子：
7.3
通讯作者：
Valentine, MT
中科院分区：
文献类型：
--
作者：
Cramer, RD;Poss, MA;Valentine, MT
生物均衡原理形状相似的分子比其他分子更有可能具有相同的生物学特性长期以来一直有助于指导药物的发现。在回顾性研究中，已经发现基于每个分子的单个规则生成的“拓扑异构体”构象的形状比较的该原理的算法实现是最一致地预测相似生物学性质的描述符，并且也非常适合于搜索潜在反应产物的大（>10（12））“虚拟文库”。因此，进行了这种形状相似性搜索方法的前瞻性试验，合成了425种化合物，并测试了它们对血管紧张素II（A-II）结合的抑制作用。通过形状搜索被鉴定为与四种查询结构中的任何一种最相似的63种化合物包括发现具有高活性的所有七种化合物，而其他362种结构中没有一种是高活性的（p < 0.001）。在所有425种化合物中，在与最近查询结构的形状相似程度和观察到的各种活性水平的频率之间发现了额外的一致关系（p < 0.05）。已知的“SAR”（规定A-II拮抗作用所需结构特征的规则）也在63种形状相似结构的生物学数据中重新生成。
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.