Ligand pose and orientational sampling in molecular docking.
Ligand pose and orientational sampling in molecular docking.
复制标题
分子对接中的配体姿势和定向抽样。
DOI：
10.1371/journal.pone.0075992
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shoichet BK
中科院分区：
文献类型：
--
作者：
Coleman RG;Carchia M;Sterling T;Irwin JJ;Shoichet BK
分子对接仍然是一个重要的工具，基于结构的筛选，以寻找新的配体和化学探针。随着对接目标的增长，包括新的评分函数项，并解决更多的目标，方向采样的可靠性和可扩展性，以及该方法的吞吐量，变得紧迫。在这里，我们探讨了消除DOCK3.6中随机行为的采样技术，使我们能够优化方向定期变量采样的方法。这也使我们能够集中精力优化代码以提高效率，使程序的速度提高了三倍。这反过来又促进了在多个采样水平上对有用诱饵目录-增强型（DUD-E）基准集的102个目标、22，805个配体和1，411，214个诱饵进行广泛测试。令人鼓舞的是，我们观察到，随着取样从50增加到500，到2000，到5000，到20000，结合位点的分子取向（因此，每个靶的平均原子得分约为1×1010至4×1010至1×1011至2×1011至5×1011，因为每个方向都有多种构象采样），对于大多数DUD-E靶，配体相对于诱饵的富集单调增加。同时，将内静电引入配体构象能的计算中，并将芳香羟基限制为低能旋转异构体，进一步提高了富集值。这里用来提高代码效率的几个策略在该领域中广泛适用。
Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys - Enhanced (DUD-E) benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20000 molecular orientations in the binding site (and so from about 1×1010 to 4×1010 to 1×1011 to 2×1011 to 5×1011 mean atoms scored per target, since multiple conformations are sampled per orientation), the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
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通讯作者：
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通讯作者：
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