I50V变异对HIV-1蛋白酶抑制剂Amprenavir抗药机制的分子动力学研究  

Probing drug resistance mechanism of I50V in HIV-1 protease on inhibitor Amprenavir by using molecular dynamics simulation

作　　者：吴世亮[1] 梁志强[1] 王伟[1] 伊长虹[1] 李洪云[1] 赵娟[1] 

机构地区：[1]山东交通学院理学院,济南250357

出　　处：《原子与分子物理学报》2017年第1期130-135,共6页Journal of Atomic and Molecular Physics

基　　金：国家自然科学基金(11504206;11274206);山东省高等学校科技计划项目(J14LJ07)

摘　　要：HIV-1蛋白酶PR(HIV-1 protease)的变异对抑制剂产生抗药性,严重消弱抗艾滋病的治疗效果.I50V变异是HIV-1蛋白酶残基变异中最重要的一个.采用分子动力学模拟和溶解相互作用能方法SIE(solvated interaction energy)研究I50V变异对抑制剂APV(amprenavir)抗药机制.分子动力学分析表明I50V变异诱导HIV-1蛋白酶整体柔性的增加,影响了抑制剂与蛋白酶的相互作用.结合自由能计算表明范德华作用的下降驱动了I50V变异对APV的抗药性.基于残基的能量分解证明V50/V50'与APV的相互作用相对于野生型的I50/I50'明显减弱,诱导了抗药性.本研究能为高效的缓解抗药性抑制剂的研发提供一定的理论指导.Mutations in HIV- 1 protease（PR） have produced drug resistance on current inhibitors and weaken inhibiting efficiency of anti - HIV drugs. In all mutations, I50V mutation is the most important one. This work adopts molecular dynamics （MD） simulations and solvated interaction energy（SIE） method to study the drug resistance of ISOV mutation on Amprenavir. Dynamics analysis shows that I50V mutation strengthens overall flexibility and affects interaction of Amprenavir with residues in HIV - 1 protease. Calculation of binding free energy indicates that the decrease in van der Waals interaction of Amprenavir with HIV - 1 protease drives drug resistance of Amprenavir on the protease. The results form residue - based energy decomposition suggest that the interaction of V50/V50 in mutated PR with Amprenavir is obviously reduced relative to the wild - type PR, which implies that I50V mutation induces drug resistance. We expect that this study can provide theoretical guidance designs of potent inhibitors targeting HIV -1 protease.

关 键 词：HIV-1蛋白酶 溶解相互作用能方法 分子动力学模拟 抗药性 

分 类 号：Q641.12[生物学—生物物理学]