Assessment of programs for ligand binding affinity prediction
Assessment of programs for ligand binding affinity prediction
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DOI：
10.1002/jcc.20893
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发表时间：
2008-06-01
影响因子：
3
通讯作者：
Skolnick, Jeffrey
中科院分区：
文献类型：
--
作者：
Kim, Ryangguk;Skolnick, Jeffrey
配体与蛋白质结合自由能的预测是药物虚拟筛选和先导化合物优化的重要组成部分。为了确定当前结合自由能估计程序的质量，我们检查了FlexX，X-Score，AutoDock和BLEEP在各种情况下的结合自由能预测中的性能，包括共结晶复合物结构，配体与其非共结晶受体的交叉对接，热未折叠受体诱饵与其配体的对接，以及具有“随机化”配体诱饵的复合物结构。在任何情况下都没有一个令人满意的实验和估计的结合自由能之间的相关性在所有测试的数据集。同时，配体分子量-结合亲和力相关性与实验预测的结合亲和力相关性之间存在很强的相关性，有时程序也能正确地对配体的结合亲和力进行排序，即使配体与其受体之间的天然相互作用由于受体变形或配体随机化而基本丧失，程序也不能决定性地区分随机化的配体诱饵与其天然配体;这表明测试的程序遗漏了精确捕获特异性配体结合相互作用的重要成分。(C)2008 Wiley Periodicals，Inc.
The prediction of the binding free energy between a ligand and a protein is an important component in the virtual screening and lead optimization of ligands for drug discovery. To determine the quality of current binding free energy estimation programs, we examined FlexX, X-Score, AutoDock, and BLEEP for their performance in binding free energy prediction in various situations including cocrystallized complex structures, cross docking of ligands to their non-cocrystallized receptors, docking of thermally unfolded receptor decoys to their ligands, and complex structures with "randomized" ligand decoys. In no case was there a satisfactory correlation between the experimental and estimated binding free energies over all the datasets tested. Meanwhile, a strong correlation between ligand molecular weight-binding affinity correlation and experimental predicted binding affinity correlation was found. Sometimes the programs also correctly ranked ligands' binding affinities even though native interactions between the ligands and their receptors were essentially lost because of receptor deformation or ligand randomization, and the programs could not decisively discriminate randomized ligand decoys from their native ligands; this suggested that the tested programs miss important components for the accurate capture of specific ligand binding interactions. (C) 2008 Wiley Periodicals, Inc.