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首页> 外文期刊>Chemometrics and Intelligent Laboratory Systems >Computational study on the binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate using conventional and steered molecular dynamics simulations
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Computational study on the binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate using conventional and steered molecular dynamics simulations

机译：使用常规和操纵分子动力学模拟计算HCV NS5B与抑制剂GS-461203和底物的结合和解离机理

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摘要

The active metabolite GS-461203 of hepatitis C virus (HCV) non-structural protein 5B (NS5B) inhibitor sofosbuvir can stall RNA synthesis or replication by competitively inhibiting the natural substrate nucleoside triphosphate like UTP. Unfortunately, S282T mutant can lead to the resistance to sofosbuvir. Here, the detailed binding mechanism and unbinding process of GS-461203 and UTP to HCV NS5B were unraveled by using conventional molecular dynamics (MD) simulation and steered molecular dynamics (SMD) simulation. Our simulation results demonstrate that both polar and nonpolar interactions are favorable for GS-461203 and UTP binding. Meanwhile, we also identified the key residues responsible for GS-461203 and UTP binding in NS5B-RNA together with the three unbinding process steps including translation, reversal of base and ribose and complete divorce. The 2'-fluoro-2'-C-methyl ribose of GS-461203 can form stronger polar and nonpolar interactions with residues S282 and 1160 than UTP. The results can also explain the reason why GS-461203 can effectively be incorporated into RNA synthesis or replication. In the S282T mutant system, the binding affinity attenuation of UTP relative to wild type HCV NS5B is less than that of GS-461203. The obtained binding and unbinding mechanism of HCV NS5B with the inhibitor GS-461203 and substrate in our work will provide useful guidance for the development of new and effective HCV NS5B inhibitors with low resistance. (C) 2016 Elsevier B.V. All rights reserved.
机译：丙型肝炎病毒（HCV）非结构蛋白5B（NS5B）抑制剂sofosbuvir的活性代谢产物GS-461203可通过竞争性抑制天然底物核苷三磷酸（如UTP）来阻止RNA合成或复制。不幸的是，S282T突变体可以导致对索非布韦的耐药性。在这里，通过使用常规分子动力学（MD）模拟和操纵分子动力学（SMD）模拟，阐明了GS-461203和UTP与HCV NS5B的详细结合机理和解结合过程。我们的模拟结果表明，极性和非极性相互作用均有利于GS-461203和UTP结合。同时，我们还确定了负责NS5B-RNA中GS-461203和UTP结合的关键残基，以及三个非结合过程步骤，包括翻译，碱基和核糖的逆转以及完全离婚。与UTP相比，GS-461203的2'-氟-2'-C-甲基核糖可与残基S282和1160形成更强的极性和非极性相互作用。结果也可以解释为什么GS-461203可以有效地掺入RNA合成或复制的原因。在S282T突变体系统中，UTP相对于野生型HCV NS5B的结合亲和力衰减小于GS-461203。在我们的工作中，获得的HCV NS5B与抑制剂GS-461203和底物的结合和解离机理将为开发新型和有效的低耐药性HCV NS5B抑制剂提供有用的指导。 （C）2016 Elsevier B.V.保留所有权利。

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