Molecular dynamics simulations exploring drug resistance in HIV-1 proteases  

作　　者：GU Hui CHEN HaiFeng WEI DongQing WANG JingFang 

机构地区：[1]College of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China [2]Shanghai Centre for Systems Biomedicine, Shanghai Jiaotong University, Shanghai 200240, China [3]Shanghai Centre for Bioinformation Technology, Shanghai 200035, China

出　　处：《Chinese Science Bulletin》2010年第24期2677-2683,共7页

基　　金：supported by the National High Technology Research and Development Program of China(2006AA020406,2007AA02Z330 and2007AA02Z333);National Natural Science Foundation of China(30770502 and 30870476);Natural Science Foundation of Shanghai(10ZR1421500);as well as the State Key Laboratory of Explosion Scienceand Technology Beijing Institaute of Technology(KFJJ09-02);National Basic Research Program of China(2005CB724303)

摘　　要：Although HIV-1 subtype B still dominates the epidemic AIDS in developed countries,an increasing number of people in developing 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 S1/S1'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.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.

关 键 词：蛋白酶抑制剂 分子动力学模拟 耐药性 HIV 艾滋病毒 MD模拟 逆转录病毒 发达国家 

分 类 号：S332.3[农业科学—作物遗传育种] TG111.4[农业科学—农艺学]