Soft docking and multiple receptor conformations in virtual screening
Soft docking and multiple receptor conformations in virtual screening
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DOI：
10.1021/jm049756p
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发表时间：
2004-10-07
影响因子：
7.3
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
Ferrari, AM;Wei, BQQ;Shoichet, BK
蛋白质构象。在配体对接筛选中，变化是一个重要的考虑因素，但很难预测。解释蛋白质柔性的一个简单方法是软化配体和受体之间空间匹配的标准。更全面但更昂贵的方法是明确地对多种受体构象进行采样。在这里，这两种方法进行了比较。通过衰减Lennard-Jones势中的排斥项来创建“软”评分函数，从而允许配体和蛋白质之间更接近。标准的“硬”Lennard-Jones势用于对接到多个受体构象。针对T4溶菌酶中的两个空腔位点筛选可用化学品目录（ACD）。这些位点经历小但重要的构象变化。改变配体结合，使它们成为软对接的良好系统。还针对药物靶标醛糖还原酶筛选ACD，所述醛糖还原酶可在配体结合时经历大的构象变化。我们评估了评分函数从数据库中超过200 000个诱饵分子中识别已知配体的能力。当只使用单一受体构象时，软电位总是比硬评分函数更好地识别已知配体。相反，当使用多种受体构象时，软功能在识别已知导联方面比硬功能差。这是真实的，甚至对腔网站，尤其是真实的醛糖还原酶。为了预测性地测试多构象方法，我们筛选了ACD中优先对接到已知结合较大配体的醛糖还原酶的扩展构象的分子。六个新的分子，排名前0.66%的命中从多重构象计算，但排名相对较差的软对接计算，进行了实验测试酶抑制。这六种中有四种抑制酶，最好的IC 50为8 μ M。虽然配体可以在软对接中获得更好的分数，但诱饵也是如此。这种诱饵的改进排名可以以牺牲真正的配体为代价。
Protein conformational. change is an important consideration in ligand-docking screens, but it is difficult to predict. A simple way to account for protein flexibility is to soften the criterion for steric fit between ligand and receptor. A more comprehensive but more expensive method would be to sample multiple receptor conformations explicitly. Here, these two approaches are compared. A "soft" scoring function was created by attenuating the repulsive term in the Lennard-Jones potential, allowing for a closer approach between ligand and protein. The standard, "hard" Lennard-Jones potential was used for docking to multiple receptor conformations. The Available Chemicals Directory (ACD) was screened against two cavity sites in the T4 lysozyme. These sites undergo small but significant conformational. changes on ligand binding, making them good systems for soft docking. The ACD was also screened against the drug target aldose reductase, which can undergo large conformational changes on ligand binding. We evaluated the ability of the scoring functions to identify known ligands from among the over 200 000 decoy molecules in the database. The soft potential was always better at identifying known ligands than the hard scoring function when only a single receptor conformation was used. Conversely, the soft function was worse at identifying known leads than the hard function when multiple receptor conformations were used. This was true even for the cavity sites and was especially true for aldose reductase. To test the multiple-conformation method predictively, we screened the ACD for molecules that preferentially docked to the expanded conformation of aldose reductase, known to bind larger ligands. Six novel molecules that ranked among the top 0.66% of hits from the multiple-conformation calculation, but ranked relatively poorly in the soft docking calculation, were tested experimentally for enzyme inhibition. Four of these six inhibited the enzyme, the best with an IC50 of 8 muM. Although ligands can get better scores in soft docking, the same is also true for decoys. The improved ranking of such decoys can come at the expense of true ligands.