Development and Evaluation of an Integrated Virtual Screening Strategy by Combining Molecular Docking and Pharmacophore Searching Based on Multiple Protein Structures
Development and Evaluation of an Integrated Virtual Screening Strategy by Combining Molecular Docking and Pharmacophore Searching Based on Multiple Protein Structures
复制标题
基于多种蛋白质结构的结合分子对接和药效团搜索的综合虚拟筛选策略的开发和评估
DOI：
10.1021/ci400382r
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发表时间：
2013-09
影响因子：
5.6
通讯作者：
Hou, Tingjun
中科院分区：
文献类型：
--
作者：
Li, Youyong;Pan, Peichen;Li, Dan;Hou, Tingjun
在本研究中，我们通过整合分子对接和基于多种蛋白质结构的基于复合物的药效团搜索，开发并评估了一种新型并行虚拟筛选策略。首先，系统评估了基于 Rho 激酶 1 (ROCK1) 九种晶体结构中的任何单一结构进行分子对接或药效团搜索以区分已知 ROCK1 抑制剂和非抑制剂的能力。然后，采用朴素贝叶斯分类或递归划分技术来整合分子对接和基于ROCK1多个晶体结构的基于复合物的药效团搜索的预测，并且集成协议产生比基于任何单一ROCK1结构的分子对接或基于复合物的药效团搜索更好的性能。最后，应用经过充分验证的综合虚拟筛选方案来鉴定中药 (TCM) 中潜在的 ROCK1 抑制剂。与已知的ROCK1抑制剂相比，从中药中获得的潜在活性化合物结构新颖且多样，它们可能为强效ROCK1抑制剂的开发提供有价值的线索。
In this study, we developed and evaluated a novel parallel virtual screening strategy by integrating molecular docking and complex-based pharmacophore searching based on multiple protein structures. First, the capacity of molecular docking or pharmacophore searching based on any single structure from nine crystallographic structures of Rho kinase 1 (ROCK1) to distinguish the known ROCK1 inhibitors from noninhibitors was evaluated systematically. Then, the naı̈ve Bayesian classification or recursive partitioning technique was employed to integrate the predictions from molecular docking and complex-based pharmacophore searching based on multiple crystallographic structures of ROCK1, and the integrated protocol yields much better performance than molecular docking or complex-based pharmacophore searching based on any single ROCK1 structure. Finally, the well-validated integrated virtual screening protocol was applied to identify potential inhibitors of ROCK1 from traditional chinese medicine (TCM). The obtained potential active compounds from TCM are structurally novel and diverse compared with the known inhibitors of ROCK1, and they may afford valuable clues for the development of potent ROCK1 inhibitors.
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