Multiple drug resistant mechanisms against darunavir, amprenavir, and nelfinavir of HIV-1 PR

被引:2
|
作者
Liu, Xiaoqing [1 ]
Dai, Qi [2 ]
Xiu, Zhilong [3 ]
机构
[1] Hangzhou Dianzi Univ, Sch Sci, Hangzhou 310018, Peoples R China
[2] Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Peoples R China
[3] Dalian Univ Technol, Dept Biosci & Biotechnol, Sch Environm & Biol Sci & Technol, Dalian 116024, Peoples R China
基金
中国国家自然科学基金;
关键词
HIV-1; PR; Inhibitor; Resistance; Mutation; Molecular dynamics simulation; HUMAN-IMMUNODEFICIENCY-VIRUS; ORALLY BIOAVAILABLE INHIBITOR; MOLECULAR DYNAMIC SIMULATIONS; PROTEASE INHIBITOR; ACTIVE-SITE; PROTONATION STATE; STRUCTURAL IMPLICATIONS; CRYSTAL-STRUCTURES; VIRAL INFECTIVITY; WATER-MOLECULES;
D O I
10.1016/j.molstruc.2012.03.057
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV), which is infecting more humans and is expanding faster in the world. The illness interferes with the immune system, making people with AIDS much more likely to get infections, including opportunistic infections and tumors that do not affect people with working immune systems. HIV-1 PR is one of the major targets of anti-AIDS drug discovery. It is, therefore, necessary to develop some inhibitors against HIV-1 PR. In this work, we executed molecular dynamics (MDs) simulation of HIV-1 PR with drugs darunavir (DRV), amprenavir (APV), nelfinavir (NFV), and examined the resistant mechanism of L101, G48V, 154V, and L90M mutations of this PR, aiming at designing promising drugs. The comparative analysis suggests that the existences of dodecahydroisoquinoline ring at P1' subsite, 4-aminophenylsulfonamide at P2' subsite, and bis-tetrahydrofuranylurethane at P2 subsite are helpful for maintaining the high affinity of the inhibitor for the protease and exhibiting high potency against multiple drug resistance (MDR) mutant protease. (C) 2012 Elsevier B.V. All rights reserved.
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页码:227 / 235
页数:9
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