Multi-Conformer Ensemble Docking to Difficult Protein Targets
Multi-Conformer Ensemble Docking to Difficult Protein Targets
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DOI：
10.1021/jp506511p
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发表时间：
2015-01-22
影响因子：
3.3
通讯作者：
Smith, Jeremy C.
中科院分区：
文献类型：
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作者：
Ellingson, Sally R.;Miao, Yinglong;Smith, Jeremy C.
使用来自有用诱饵目录（DUD，ducl.clocking.org）的五种蛋白质对大规模整体对接进行了研究，事实证明对这些蛋白质进行晶体结构对接很困难。为每种蛋白质生成分子动力学轨迹，并从轨迹中提取代表性构象结构的集合。对这些选定的模拟结构和基于集合的富集因子进行对接计算，与使用相同蛋白质靶标的晶体结构中的对接或随机选择的化合物获得的结果进行比较。模拟衍生的快照具有改进的富集因子，可增加五种选定蛋白质中四种的对接命中的化学多样性。当使用对接针对困难的蛋白质靶标筛选大型化学物质库时，将从moleCtilar动力学模拟获得的所有对接结果相结合，然后选择顶级化合物，这似乎是增加命中数量和多样性的有效策略。
Large-scale ensemble docking is investigated using five proteins from the Directory Of Useful' Decoys (DUD, ducl.clocking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein, and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. Simulation-derived snapshots are found with improved enrichment factors that increase the chemical diversity of docking hits for four of the five selected proteins. A combination of all the docking results obtained from moleCtilar dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.