Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections
Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections
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DOI：
10.1073/pnas.1015024108
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发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
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作者：
Clemons, Paul A.;Wilson, J. Anthony;Schreiber, Stuart L.
利用不同的小分子集合，我们最近发现来自不同来源（商业、学术和天然）的化合物集具有不同的蛋白质结合行为，这些行为与这些化合物集的立体化学复杂性趋势相关。这些结果有助于深入了解合成化学家在合成生物发现筛选集合时可能针对的结构特征。我们报告了这些化合物的结构特性和生物性能多样性的广泛表征，并扩展了比较分析，包括物理化学特性和预测构象的三维形状。结果强调了这些集合之间额外的相似性和差异性，但也强调了这种比较对分子描述符选择的依赖性。利用蛋白质结合数据集，我们引入了一种信息论方法来评估具有特异性约束的性能多样性。这种方法不依赖于寻找单个的活性化合物，而是允许对化合物子集进行合理的判断。我们还将此措施应用于ChemBank的公开可用数据，用于不同组的功能分析中相同的化合物集。我们发现，在蛋白质结合研究和功能分析中，通过这一措施判断，化合物集的性能多样性在一系列属性值中相对稳定。由于构建具有更高性能的筛选集合依赖于合成有机化学资源的有效利用，这些研究阐明了一个重要的定量框架，以帮助在构建此类集合时优先选择。
Using a diverse collection of small molecules we recently found that compound sets from different sources (commercial; academic; natural) have different protein-binding behaviors, and these behaviors correlate with trends in stereochemical complexity for these compound sets. These results lend insight into structural features that synthetic chemists might target when synthesizing screening collections for biological discovery. We report extensive characterization of structural properties and diversity of biological performance for these compounds and expand comparative analyses to include physicochemical properties and three-dimensional shapes of predicted conformers. The results highlight additional similarities and differences between the sets, but also the dependence of such comparisons on the choice of molecular descriptors. Using a protein-binding dataset, we introduce an information-theoretic measure to assess diversity of performance with a constraint on specificity. Rather than relying on finding individual active compounds, this measure allows rational judgment of compound subsets as groups. We also apply this measure to publicly available data from ChemBank for the same compound sets across a diverse group of functional assays. We find that performance diversity of compound sets is relatively stable across a range of property values as judged by this measure, both in protein-binding studies and functional assays. Because building screening collections with improved performance depends on efficient use of synthetic organic chemistry resources, these studies illustrate an important quantitative framework to help prioritize choices made in building such collections.