Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations
Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations
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DOI：
10.1021/jm001044l
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发表时间：
2000-12-14
影响因子：
7.3
通讯作者：
Rognan, D
中科院分区：
文献类型：
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作者：
Bissantz, C;Folkers, G;Rognan, D
三种不同的数据库对接程序（Dock、FlexX、Gold）与七种评分函数（Chemscore、Dock、FlexX、Fresno、Gold、Pmf、Score）结合使用，以评估针对已知三维结构的两种蛋白质靶点（胸苷激酶、雌激素受体）的虚拟筛选方法的准确性。对于这两种靶，通常可以从990个配体的随机数据库中辨别出10个真实命中中的约7个。使用两个或三个评分函数共有的共识列表明显地提高了前5%评分者的命中率，从10%（单评分）提高到25-40%（双评分）和65-70%（三评分）。然而，在所有测试的情况下，没有明确的关系，可以找到对接和排名精度之间。此外，无论实现对接准确度和使用评分函数如何，预测真实命中的绝对结合自由能都是不可能的。由于最佳对接/共识评分组合随所选靶标和靶标-配体相互作用的物理化学而变化，因此我们提出了一种用于筛选大型数据库的两步方案：（i）筛选包含一些已知配体的简化数据集，以获得最佳对接/共识评分方案，（ii）将后者参数应用于整个数据库的筛选。
Three different database docking programs (Dock, FlexX, Gold) have been used in combination with seven scoring functions (Chemscore, Dock, FlexX, Fresno, Gold, Pmf, Score) to assess the accuracy of virtual screening methods against two protein targets (thymidine kinase, estrogen receptor) of known three-dimensional structure. For both targets, it was generally possible to discriminate about 7 out of 10 true hits from a random database of 990 ligands. The use of consensus lists common to two or three scoring functions clearly enhances hit rates among the top 5% scorers from 10% (single scoring) to 25-40% (double scoring) and up to 65-70% (triple scoring). However, in all tested cases, no clear relationships could be found between docking and ranking accuracies. Moreover, predicting the absolute binding free energy of true hits was not possible whatever docking accuracy was achieved and scoring function used. As the best docking/consensus scoring combination varies with the selected target and the physicochemistry of target-ligand interactions, we propose a two-step protocol for screening large databases: (i) screening of a reduced dataset containing a few known Ligands for deriving the optimal docking/consensus scoring scheme, (ii) applying the latter parameters to the screening of the entire database.