Molecular dynamics simulations exploring drug resistance in HIV-1 proteases

• Published in: Chinese science bulletin 2010-08, Vol.55 (24), p.2677-2683
• Main Authors: Gu, Hui, Chen, HaiFeng, Wei, DongQing, Wang, JingFang
• Format: Article
• Language: English
• Subjects: Chemistry/Food Science; Earth Sciences; Engineering; HIV; Humanities and Social Sciences; Life Sciences; MD模拟; multidisciplinary; Physics; Science; Science (multidisciplinary); 分子动力学模拟; 发达国家; 耐药性; 艾滋病毒; 蛋白酶抑制剂; 逆转录病毒
• ISSN: 1001-6538; 1861-9541
• DOI: 10.1007/s11434-010-3257-6

Although HIV-1 subtype B still dominates the epidemic AIDS in developed countries, an increasing number of people in devel- oping countries are suffering from an epidemic of non-subtype B viruses. What is worse, the efficacy of the combinational use of antiretroviral drugs is gradually compromised by the rapid development of drug resistance. To gain an insight into drug resistance, 10-ns MD simulations were simultaneously conducted on the complexes of the TL-3 inhibitor with 4 different proteases （Bwt, Bmut, Fwt and Fmut）, among which the complex of the Bwt protease with the TL-3 inhibitor was treated as the control group. Detailed analyses of MD data indicated that the drug resistance of Bmut against TL-3 mainly derived from loss of an important hydrogen bond and that of Fwt was caused by the decrease of hydrophobic interactions in S 1/S 1＇ pocket, while both of the two reasons mentioned above were the cause of the Fmut protease＇s resistance. These results are in good agreement with the previous experiments, revealing a possible mechanism of drug resistance for the aforementioned protease subtypes against the TL-3 inhibitor. Additionally, another indication was obtained that the mutations of M36I, V82A and L90M may induce structural transforms so as to alter the inhibitor＇s binding mode.