Decoys for docking
Decoys for docking
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DOI：
10.1021/jm0491187
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发表时间：
2005-06-02
影响因子：
7.3
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
Graves, AP;Brenk, R;Shoichet, BK
分子对接被广泛用于预测新的药物发现先导化合物。成功取决于对接评分功能的质量以及其他因素。一个不完美的评分函数可以误导预测不正确的配体几何形状或选择非结合分子的真正的配体。这些假阳性命中可以被认为是“诱饵”。虽然这些诱饵令人沮丧，但它们可能为对接算法提供重要的测试;诱饵越微妙，测试就越严格。事实上，诱饵数据库已被用于改进蛋白质结构预测算法和蛋白质-蛋白质对接算法。在这里，我们描述了五种酶中的20种几何诱饵和166种“命中列表”诱饵，分子预测结合我们的对接程序进行了测试，并发现没有这样做β-内酰胺酶和两个空腔网站溶菌酶。特别是在非常简单的空洞部位，这些诱饵突出了我们的评分函数中的特定弱点。我们还考虑了其他五个广泛使用的对接评分功能对我们的几何和命中列表诱饵的性能。有趣的是，尽管许多其他评分函数在几何诱饵上表现得更好，但它们在命中列表诱饵上的表现通常更差，这些诱饵通常是高度排名的分子，这些分子似乎与模型位点互补性很差。对其他评分函数中的几个“命中”进行了实验测试，发现实际上是诱饵。总的来说，这些诱饵为分子对接评分功能的开发和改进提供了工具。这样的改进，反过来，可以快速测试实验对这些和相关的实验系统，这是表现良好的测定和结构确定。
Molecular docking is widely used to predict novel lead compounds for drug discovery. Success depends on the quality of the docking scoring function, among other factors. An imperfect scoring function can mislead by predicting incorrect ligand geometries or by selecting nonbinding molecules over true ligands. These false-positive hits may be considered "decoys". Although these decoys are frustrating, they potentially provide important tests for a docking algorithm; the more subtle the decoy, the more rigorous the test. Indeed, decoy databases have been used to improve protein structure prediction algorithms and protein-protein docking algorithms. Here, we describe 20 geometric decoys in five enzymes and 166 "hit list" decoys-i.e., molecules predicted to bind by our docking program that were tested and found not to do so-for beta-lactamase and two cavity sites in lysozyme. Especially in the cavity sites, which are very simple, these decoys highlight particular weaknesses in our scoring function. We also consider the performance of five other widely used docking scoring functions against our geometric and hit list decoys. Intriguingly, whereas many of these other scoring functions performed better on the geometric decoys, they typically performed worse on the hit list decoys, often highly ranking molecules that seemed to poorly complement the model sites. Several of these "hits" from the other scoring functions were tested experimentally and found, in fact, to be decoys. Collectively, these decoys provide a tool for the development and improvement of molecular docking scoring functions. Such improvements may, in turn, be rapidly tested experimentally against these and related experimental systems, which are well-behaved in assays and for structure determination.