Accounting for Target Flexibility and Water Molecules by Docking to Ensembles of Target Structures: The HCV NS5B Palm Site I Inhibitors Case Study
Accounting for Target Flexibility and Water Molecules by Docking to Ensembles of Target Structures: The HCV NS5B Palm Site I Inhibitors Case Study
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DOI：
10.1021/ci400367m
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发表时间：
2014-02-01
影响因子：
5.6
通讯作者：
Cecchetti, Violetta
中科院分区：
文献类型：
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作者：
Barreca, Maria Letizia;Iraci, Nunzio;Cecchetti, Violetta
在治疗中引入新的抗HCV药物是迫切需要的，并且对于开发无干扰素治疗是必要的。因此，病毒NS 5 B聚合酶的新型小分子抑制剂的发现和开发代表了许多制药公司和学术团体令人兴奋的研究领域。这项研究代表了对这一领域的贡献，并依赖于最佳NS 5 B模型的鉴定，该模型将用于基于结构的计算方法，旨在鉴定蛋白质变构位点之一（即棕榈位点I）的新型非核苷抑制剂。首先，NS 5 B抑制剂在棕榈网站I被分类为水介导或非水介导的配体，这取决于它们的能力，以相互作用或取代一个特定的水分子。然后，我们利用现有的X-射线结构的NS 5 B/配体复合物，建立不同的蛋白质/水的组合模型，这是用来调查对接研究的溶剂位点的影响，以及蛋白质构象的影响。作为总体趋势，我们观察到通过包含明确的水分子，水介导的抑制剂的对接结果的性能得到改善，而非水介导的抑制剂通常会发生相反的行为。然后将两个配体组的最佳表现靶结构用于含有已知NS 5 B抑制剂沿着相关诱饵的文库的虚拟筛选模拟，以基于它们区分活性和非活性化合物以及产生正确结合模式的能力来评估最佳表现靶集合。不同蛋白质结构/水集合的平行使用优于单一靶结构的使用，双蛋白3 H98/2 W-2FVC/7 W和3 HKY/NoW-3SKE/NoW模型分别产生水介导的抑制剂和非水介导的抑制剂的最佳性能集合。从这项工作中收集的信息证实了水分子和蛋白质灵活性在基于对接的研究中的主要作用，并可用于帮助NS 5 B导向的HCV药物发现工作。
The introduction of new anti-HCV drugs in therapy is an imperative need and is necessary with a view to develop an interferon-free therapy. Thus, the discovery and development of novel small molecule inhibitors of the viral NS5B polymerase represent an exciting area of research for many pharmaceutical companies and academic groups. This study represents a contribution to this field and relies on the identification of the best NS5B model(s) to be used in structure-based computational approaches aimed at identifying novel non-nucleoside inhibitors of one of the protein allosteric sites, namely, palm site I. First, the NS5B inhibitors at palm site I were classified as water-mediated or nonwater-mediated ligands depending on their ability to interact with or displace a specific water molecule. Then, we took advantage of the available X-ray structures of the NS5B/ligand complexes to build different models of protein/water combinations, which were used to investigate the influence on docking studies of solvent sites as well as of the influence of the protein conformations. As the overall trend, we observed improved performance in the docking results of the water-mediated inhibitors by inclusion of explicit water molecules, with an opposite behavior generally happening for the nonwater-mediated inhibitors. The best performing target structures for the two ligand sets were then used for virtual screening simulations of a library containing the known NS5B inhibitors along with related decoys to assess the best performing targets ensembles on the basis of their ability to discriminate active and inactive compounds as well as to generate the correct binding modes. The parallel use of different protein structures/water sets outperformed the use of a single target structure, with the two-protein 3H98/2W-2FVC/7W and 3HKY/NoW-3SKE/NoW models resulting in the best performing ensembles for water-mediated inhibitors and nonwater-mediated inhibitors, respectively. The information gathered from this work confirms the primary role of water molecules and protein flexibility in docking-based studies and can be exploited to aid NS5B-directed HCV drug discovery efforts.