Computational simulations of HIV-1 proteases-multi-drug resistance due to nonactive site mutation L90M
Computational simulations of HIV-1 proteases-multi-drug resistance due to nonactive site mutation L90M
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DOI：
10.1021/ja060682b
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发表时间：
2006-06-21
影响因子：
15
通讯作者：
Hoshino, Tyuji
中科院分区：
文献类型：
--
作者：
Ode, Hirotaka;Neya, Saburo;Hoshino, Tyuji
人类免疫缺陷病毒1型蛋白酶（HIV-1 PR）是目前可用的抗HIV-1药物靶向的蛋白质之一。HIV-1 PR的抑制剂已经出现，它们降低了发达国家获得性免疫缺陷综合征（AIDS）的死亡率。然而，抗药性HIV-1变种的出现率相当高，因为它们的逆转录病毒生命周期短，突变率高。针对HIV-1 PR抑制剂（PI）的严重耐药突变经常出现在PR的活性位点。例外的是，一些其他突变如L90 M引起耐药，尽管这些突变出现在非活性位点。由于非活性位点突变引起的耐药机制难以解释。在这项研究中，我们对L90 M PR与三种抑制剂和一种典型底物的复合物进行了计算模拟，并阐明了耐药机制。L90 M突变导致第90个残基的侧链原子与第25个残基的主链原子之间的相互作用发生变化，第25个残基的轻微错位导致第84个残基处的侧链旋转。第84个残基的旋转导致抑制剂从适当的结合位置移位，导致与瓣或环区域的碰撞。从能量和结构的角度解释了对三种抑制剂的抗性水平的差异，这为有前途的药物即使对L90 M突变体也保持其功效提供了建议。
Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the proteins that currently available anti-HIV-1 drugs target. Inhibitors of HIV-1 PR have become available, and they have lowered the rate of mortality from acquired immune deficiency syndrome (AIDS) in advanced countries. However, the rate of emergence of drug-resistant HIV-1 variants is quite high because of their short retroviral life cycle and their high mutation rate. Serious drug- resistant mutations against HIV-1 PR inhibitors (PIs) frequently appear at the active site of PR. Exceptionally, some other mutations such as L90M cause drug resistance, although these appear at nonactive sites. The mechanism of resistance due to nonactive site mutations is difficult to explain. In this study, we carried out computational simulations of L90M PR in complex with each of three kinds of inhibitors and one typical substrate, and we clarified the mechanism of resistance. The L90M mutation causes changes in interaction between the side chain atoms of the 90th residue and the main chain atoms of the 25th residue, and a slight dislocation of the 25th residue causes rotation of the side chain at the 84th residue. The rotation of the 84th residue leads to displacement of the inhibitor from the appropriate binding location, resulting in a collision with the flap or loop region. The difference in levels of resistance to the three inhibitors has been explained from energetic and structural viewpoints, which provides the suggestion for promising drugs keeping its efficacy even for the L90M mutant.