Management of Hepatitis C virus infection changed after the development of direct‐acting antiviral agents, including NS5B polymerase inhibitors. However, the presence of non‐synonymous substitutions could lead to therapy failure. Herein, we analyzed novel polymorphism clusters in NS5B polymerase from Hepatitis C virus (HCV) subtype 1b isolates of direct‐acting antivirals (DAAs) naïve patients by Sanger population sequencing. By means of computational approaches, we investigated the impact of these polymorphisms on the apo‐polymerase stability and on the binding affinity of dasabuvir and setrobuvir. Our thermodynamic and structural analysis highlighted that some mutational patterns could enhance or reduce the drug's affinity if compared to the wild‐type complexes and allowed us to well characterize the binding mode of the known drugs into the NS5B binding pocket. Our computational findings agreed with dasabuvir and setrobuvir in vitro reduced binding affinities against C316N mutant and could be useful in guiding the therapeutic approaches in presence of specific natural polymorphisms on HCV polymerase.

中文翻译：

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从直接作用的抗病毒幼稚患者中分离出的新的HCV聚合酶多态性簇的结构模型：专注于Dasabuvir和Setrobuvir的结合亲和力

在开发出包括NS5B聚合酶抑制剂在内的直接作用抗病毒药物后，丙型肝炎病毒感染的管理发生了变化。但是，非同义替代的存在可能导致治疗失败。本文中，我们通过Sanger人群测序分析了来自直接作用抗病毒药物（DAA）的丙型肝炎病毒（HCV）1b亚型分离株的NS5B聚合酶中的新型多态性簇。通过计算方法，我们研究了这些多态性对脱辅基聚合酶稳定性以及达沙布韦和塞特布韦的结合亲和力的影响。我们的热力学和结构分析强调，某些突变模式可以增强或降低药物的 与野生型复合物相比具有s的亲和力，使我们能够很好地表征已知药物在NS5B结合口袋中的结合方式。我们的计算结果与dasabuvir和setrobuvir一致体外降低了对C316N突变体的结合亲和力，在HCV聚合酶存在特定天然多态性的情况下，可用于指导治疗方法。