Exploring drug-resistant mechanisms of I84V mutation in HIV-1 protease toward different inhibitors by thermodynamics integration and solvated interaction energy method
Exploring drug-resistant mechanisms of I84V mutation in HIV-1 protease toward different inhibitors by thermodynamics integration and solvated interaction energy method
复制标题
利用热力学积分和溶剂化相互作用能法探讨HIV-1蛋白酶I84V突变对不同抑制剂的耐药机制
DOI：
10.1016/j.cplett.2018.06.040
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发表时间：
2018-08-16
影响因子：
2.8
通讯作者：
Chen, Jianzhong
中科院分区：
文献类型：
--
作者：
Gao, Ya;Zhu, Tong;Chen, Jianzhong
HIV-1蛋白酶（PR） I84V突变对多种抑制剂产生耐药性。采用热力学积分法（TI）、溶剂化相互作用能法（SIE）和动力学分析方法比较探讨了I84V突变对4种抑制剂的耐药机制。动态分析表明，在I84V突变体中，PR的皮瓣更灵活，PR的皮瓣附近的结构域和84/84'残基也发生了明显的变化。结合自由能预测表明I84V突变主要驱动抑制剂与PR的范德华相互作用的减少，该研究有望为设计针对HIV-1蛋白酶的有效抑制剂提供理论帮助。(C) 2018 Elsevier B.V.版权所有
I84V mutation in HIV-1 protease (PR) has produced drug resistance on multiple inhibitors. Thermodynamic integration (TI), solvated interaction energy (SIE) and dynamic analysis were applied to comparatively probe drug-resistant mechanisms of I84V mutation toward four inhibitors. Dynamic analysis suggests that in the I84V mutants the flaps of PR are more flexible and domains near the flaps of PR and residues 84/84' also change obviously. Binding free energy predictions show I84V mutation mainly drive the decrease in van der Waals interactions of inhibitors with PR. This study is expected to provide theoretical helps for designs of potent inhibitors targeting HIV-1 protease. (C) 2018 Elsevier B.V. All rights reserved.