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.
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)
