NS3 protease plays a vital role in the replication of the hepatitis C virus (HCV). BMS-605339 is a novel linear tetra-peptide α-ketoamide inhibitor of NS3 protease and shows specificity for HCV NS3 protease genotype 1a and genotype 1b. Mutation at the key site 168 of the HCV NS3 protease can induce resistance to BMS-605339, which greatly affects the antiviral therapy efficacy to hepatitis C. In the present study, we employed molecular dynamics simulations, free energy calculations, and free energy decomposition to explore the drug resistance mechanism of BMS-605339 due to the three representative mutations D168C/Y/V. The free energy decomposition analysis indicates that the decrease in the binding affinity is mainly attributed to the decrease in both van der Waals and electrostatic interactions. After detailed analysis of our calculated results, we observed that the break of the salt bridge between residues 155 and 168 caused by the mutations D168C/Y/V is the original reason for the decrease in the binding ability between BMS-605339 and the mutant NS3 proteases. The obtained results will reveal the drug resistance mechanism between BMS-605339 and the mutant NS3 proteases, and provide valuable clue for designing novel and more potent drugs to HCV NS3 protease.

中文翻译：

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HCV NS3蛋白酶对BMS-605339耐药机制的计算研究。

NS3蛋白酶在丙型肝炎病毒（HCV）的复制中起着至关重要的作用。BMS-605339是NS3蛋白酶的新型线性四肽α-酮酰胺抑制剂，对HCV NS3蛋白酶基因型1a和基因型1b具有特异性。HCV NS3蛋白酶关键位点168的突变可诱导对BMS-605339的抗药性，这极大地影响了对丙型肝炎的抗病毒治疗效果。在本研究中，我们采用分子动力学模拟，自由能计算和自由能分解来探索由于三个代表性突变D168C / Y / V而引起的BMS-605339的耐药机制。自由能分解分析表明结合亲和力的降低主要归因于范德华力和静电相互作用的降低。在对我们的计算结果进行详细分析之后，我们观察到由突变D168C / Y / V引起的残基155和168之间盐桥的断裂是BMS-605339与突变NS3蛋白酶之间结合能力降低的最初原因。所得结果将揭示BMS-605339与突变型NS3蛋白酶之间的耐药机制，并为设计新型更有效的HCV NS3蛋白酶药物提供有价值的线索。