Ensemble Docking into Multiple Crystallographically Derived Protein Structures: An Evaluation Based on the Statistical Analysis of Enrichments
Ensemble Docking into Multiple Crystallographically Derived Protein Structures: An Evaluation Based on the Statistical Analysis of Enrichments
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DOI：
10.1021/ci900407c
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发表时间：
2010-04-01
影响因子：
5.6
通讯作者：
Spiegel, Katrin
中科院分区：
文献类型：
--
作者：
Craig, Ian R.;Essex, Jonathan W.;Spiegel, Katrin
已经提出并采用了对接多个受体构象（“整体对接”），希望它可以解释虚拟筛选中的受体灵活性，从而提供比对接单个刚性受体结构更高的富集度。本文提出的统计分析提供了定量证据，表明在某些情况下，对接到晶体学衍生的构象系综确实比对接到系综的任何单个成员产生更好的富集。然而，这些“成功”的整体仅占所检查的一小部分，并且不可能仅使用蛋白质结构信息来前瞻性地预测它们的身份。更常见的结果是，整体丰富度高于其单个成员提供的丰富度的平均值。另一个有希望的发现是，如果有一组已知的活性化合物可用，那么基于诱导拟合对接的方法似乎是构建提供相对高富集度的整体的可靠方法。
Docking into multiple receptor conformations ("ensemble docking") has been proposed, and employed, in the hope that it may account for receptor flexibility in virtual screening and thus provide higher enrichments than docking into single rigid receptor structures. The statistical analyses presented in this paper provide quantitative evidence that in some cases docking into a crystallographically derived conformational ensemble does indeed yield better enrichment than docking into any of the individual members of the ensemble. However, these "successful" ensembles account for only a minority of those examined and it would not have been possible to prospectively predict their identity using only protein structural information. A more frequently observed outcome is that the ensemble enrichment is higher than the mean of the enrichments provided by its individual members. An additional and promising finding is that, if a set of known active compounds is available, an approach based on induced-fit docking appears to be a reliable way to construct ensembles which provide relatively high enrichments.