Do structurally similar molecules have similar biological activity?
Do structurally similar molecules have similar biological activity?
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DOI：
10.1021/jm020155c
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发表时间：
2002-09-12
影响因子：
7.3
通讯作者：
Traphagen, LM
中科院分区：
文献类型：
--
作者：
Martin, YC;Kofron, JL;Traphagen, LM
为了设计多样化的组合文库或选择多样化的化合物以增加筛选集合，计算化学家经常拒绝与已经选择用于组合文库或筛选集合的化合物相似度大于或等于0.85的化合物。使用日光指纹，该报告显示，对于作为115个高通量筛选试验的后续测定的IC50值，与活性物质相似的大于或等于0.85（Tanimoto）的化合物本身具有活性的可能性仅为30%。尽管这种富集大于随机筛选和与三维结构对接所发现的富集，但相似化合物中活性成分的这种低分数不仅是因为日光指纹和Tanimoto相似性计算的缺陷，而且还因为相似化合物不一定以相似的方式与靶大分子相互作用。目前的研究强调库设计的统计或概率性质，不能期望完美的结果。
To design diverse combinatorial libraries or to select diverse compounds to augment a screening collection, computational chemists frequently reject compounds that are greater than or equal to0.85 similar to one already chosen for the combinatorial library or in the screening set. Using Daylight fingerprints, this report shows that for IC50 values determined as a follow-up to 115 high-throughput screening assays, there is only a 30% chance that a compound that is greater than or equal to 0.85 (Tanimoto) similar to an active is itself active. Although this enrichment is greater than that found with random screening and docking to three-dimensional structures, this low fraction of actives within similar compounds occurs not only because of deficiencies in the Daylight fingerprints and Tanimoto similarity calculations but also because similar compounds do not necessarily interact with the target macromolecule in similar ways. The current study emphasizes the statistical or probabilistic nature of library design and that perfect results cannot be expected.