Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease
Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease
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HCV NS3/4A蛋白酶V36M、R155K、V36M R155K、T54A、A156T突变导致Narlaprevir耐药分子机制的计算研究
DOI：
10.1139/bcb-2014-0039
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发表时间：
2014-07
影响因子：
2.9
通讯作者：
Mingjuan Ji
中科院分区：
文献类型：
--
作者：
Huiqun Wang;Lingling Geng;Bo-Zhen Chen;Mingjuan Ji
那拉普雷韦是一种新型的丙型肝炎病毒NS3/4A蛋白水解酶抑制剂，最近已进入II期临床试验。然而，已发现纳拉普韦具有明显的耐药性。本研究通过分子动力学模拟、自由能计算和自由能分解分析，研究了NS3/4A蛋白水解酶基因V36M、R155K、V36M+R155K、T54A和A156T突变导致纳拉帕韦耐药的分子机制。对野生型和5个突变体的预测结合自由能表明，突变V36M、R155K和T54A导致低水平的耐药性，突变V36M+R155K和A156T导致高水平的耐药性，这与实验数据一致。对单个能量项的分析表明，范德华贡献对于区分这六个络合物的结合亲和力是重要的。这些发现再次表明，不同分子的结合是有效的。
Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecu...
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影响因子：
15
作者：
Junmei Wang;Paul Morin;Wei Wang;P. Kollman
通讯作者：
Junmei Wang;Paul Morin;Wei Wang;P. Kollman
影响因子：
4.9
作者：
Malcolm, BA;Liu, R;Njoroge, FG
通讯作者：
Njoroge, FG
影响因子：
3
作者：
Gohlke, H;Case, DA
通讯作者：
Case, DA
影响因子：
4.4
作者：
Hou, TJ;McLaughlin, W;Wang, W
通讯作者：
Wang, W
影响因子：
3
作者：
J. Weiser;P. Shenkin;W. Still
通讯作者：
J. Weiser;P. Shenkin;W. Still