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首页> 外文期刊>Journal of Medicinal Chemistry >Toward general methods of targeted library design: topomer shape similarity searching with diverse structures as queries.
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Toward general methods of targeted library design: topomer shape similarity searching with diverse structures as queries.

机译：面向目标库设计的一般方法：以不同结构作为查询的拓扑异构体形状相似性搜索。

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摘要

A promising strategy for selecting synthetic targets is similarity-based searching of very large "virtual libraries", which comprise all structures accessible by linking two or three commercially available building blocks with combinatorial syntheses. To assess the general applicability of this strategy, leading structures taken from each of 34 recent medicinal chemistry publications were used as queries to search a virtual library containing 2.6 x 10(13) products from seven reactions, using a topomer shape similarity metric. Eighty-five percent of these searches succeeded, by yielding, with a search radius no greater than 120 topomer shape units, either at least 400 hits or hits from at least six sublibraries. From these 34 sets of search results, 122 representative structures were selected, illustrating potential "lead hops", or otherwise novel structures. Overall shape similarity to the query structure was confirmed for up to 95% of these representative structures, according to FLEXS, an algorithmically distinct program. Experimentally, there were 28 structures among those reported in the 34 query publications that were identified within the virtual library. Among these, the frequency of high activity was 87% for the 16 structures whose similarity to their query was 90 topomer units or less, compared to a frequency of 50% for the other 12 structures.
机译：选择合成靶标的一种有前途的策略是对非常大的“虚拟库”进行基于相似度的搜索，该库包括通过将两个或三个商业上可用的构建基块与组合合成物连接起来而可访问的所有结构。为了评估该策略的一般适用性，使用拓扑异构体形状相似性度量标准，从34个近期药物化学出版物中的每一个中获取的主要结构用作查询，以搜索包含来自七个反应的2.6 x 10（13）产物的虚拟文库。这些搜索中的百分之八十五通过产生不超过120个拓扑单体形状单位的搜索半径而成功完成了至少400次命中或至少六个子库的命中。从这34组搜索结果中，选择了122个代表性结构，这些结构说明了潜在的“铅跃点”或其他新颖结构。根据FLEXS（一种算法独特的程序），可以确定高达95％的代表性结构与查询结构的总体形状相似性。实验上，在虚拟库中识别的34个查询出版物中报告的结构中，有28种结构。其中，与其查询相似度为90个拓扑单元或更少的16个结构的高活性频率为87％，而其他12个结构的高活性频率为50％。

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