Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes
Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes
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DOI：
10.1021/jm0300330
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发表时间：
2003-07-03
影响因子：
7.3
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
McGovern, SL;Shoichet, BK
分子对接使用受体的三维结构来筛选潜在配体的小分子数据库。对接屏幕上的结合位点的构象的依赖性仍然是一个悬而未决的问题。为了评价随着活性位点构象变得不太明确而发生的信息损失，将小分子数据库对接到10个不同酶结合位点的holo（配体结合）、apo和同源性建模结构。全息和载脂蛋白表示是取自蛋白质数据库（PDB）的晶体结构，同源建模结构取自公共资源ModBase。对接的数据库是MDL药物数据报告（MDDR），这是一个包含95000个小分子的功能注释数据库，其中包含10个系统中每个系统的至少35个配体。在所有位点中，MDDR中至少99%的分子被视为非结合性诱饵。对于每个系统，使用holo、apo和建模结构筛选MDDR，并评价每个结构在随机选择中富集该系统的已知配体的能力。最好的整体富集是由七个系统中的全息结构，两个系统中的载脂蛋白结构和一个系统中的模型结构产生的。这些结果表明，对接计算的性能受到屏幕中使用的受体的特定表示的影响，并且全息结构是最有可能产生已知配体和诱饵分子之间的最佳区分的结构，但是这项研究也出现了这一规则的重要例外。虽然每一个全息，载脂蛋白，和建模的构象导致已知的配体在所有系统中的富集，富集并不总是上升到一个水平，判断为足以证明对接屏幕的努力。使用20倍富集的已知配体随机选择作为一个粗略的指导方针，什么可能是足以证明对接屏幕，全息构象的酶符合这一标准的10个网站中的8个，而载脂蛋白构象符合这一标准，只有两个网站和建模的构象在三个。
Molecular docking uses the three-dimensional structure of a receptor to screen a small molecule database for potential ligands. The dependence of docking screens on the conformation of the binding site remains an open question. To evaluate the information loss that occurs as the active site conformation becomes less defined, a small molecule database was docked against the holo (ligand bound), apo, and homology modeled structures of 10 different enzyme binding sites. The holo and apo representations were crystallographic structures taken from the Protein Data Bank (PDB), and the homology-modeled structures were taken from the publicly available resource ModBase. The database docked was the MDL Drug Data Report (MDDR), a functionally annotated database of 95 000 small molecules that contained at least 35 ligands for each of the 10 systems. In all sites, at least 99% of the molecules in the MDDR were treated as nonbinding decoys. For each system, the holo, apo, and modeled structures were used to screen the MDDR, and the ability of each structure to enrich the known ligands for that system over random selection was evaluated. The best overall enrichment was produced by the holo structure in seven systems, the apo structure in two systems, and the modeled structure in one system. These results suggest that the performance of the docking calculation is affected by the particular representation of the receptor used in the screen, and that the holo structure is the one most likely to yield the best discrimination between known ligands and decoy molecules, but important exceptions to this rule also emerge from this study. Although each of the holo, apo, and modeled conformations led to enrichment of known ligands in all systems, the enrichment did not always rise to a level judged to be sufficient to justify the effort of a docking screen. Using a 20-fold enrichment of known ligands over random selection as a rough guideline for what might be enough to justify a docking screen, the holo conformation of the enzyme met this criterion in eight of 10 sites, whereas the apo conformation met this criterion in only two sites and the modeled conformation in three.