Abstract：
Current management of HCV infection is based on Direct-Acting Antiviral Drugs (DAAs). However, resistance-associated mutations, especially in the NS3 and NS5B regions are gradually decreasing the efficacy of DAAs. Among the most effective HCV NS3/4A protease drugs, Sofosbuvir also develops resistance due to mutations in the NS3 and NS5B regions. Four mutations at positions A156Y, L36P, Q41H, and Q80K are classified as high-level resistance mutations. The resistance mechanism of HCV NS3/4A protease toward Sofosbuvir caused by these mutations is still unclear, as there is less information available regarding the structural and functional effects of the mutations against Sofosbuvir. In this work, we combined molecular dynamics simulation, molecular mechanics/Generalized-Born surface area calculation, principal component analysis, and free energy landscape analysis to explore the resistance mechanism of HCV NS3/4A protease due to these mutations, as well as compare interaction changes in wild-type. Subsequently, we identified that the mutant form of HCV NS3/4A protease affects the activity of Sofosbuvir. In this study, the resistance mechanism of Sofosbuvir at the atomic level is proposed. The proposed drug-resistance mechanism will provide valuable guidance for the design of HCV drugs.
摘要：
HCV感染的当前管理基于直接作用抗病毒药物(DAA)。然而,抗性相关突变，特别是在NS3和NS5B区域DAA的功效正在逐步降低。在最有效的HCVNS3/4A蛋白酶药物中，Sofosbuvir还由于NS3和NS5B区域中的突变而产生抗性。A156Y位置的四个突变，L36P,Q41H,和Q80K被分类为高水平抗性突变。这些突变引起的HCVNS3/4A蛋白酶对Sofosbuvir的耐药机制尚不清楚。因为关于Sofosbuvir突变的结构和功能影响的信息较少。在这项工作中,我们结合了分子动力学模拟，分子力学/广义玻恩表面积计算,主成分分析，和自由能景观分析，探讨HCVNS3/4A蛋白酶由于这些突变的耐药机制，以及比较野生型的相互作用变化。随后，我们发现HCVNS3/4A蛋白酶的突变形式影响Sofosbuvir的活性.在这项研究中,提出了索非布韦在原子水平上的抗性机制。提出的耐药机制将为HCV药物的设计提供有价值的指导。
