Molecular dynamics simulations exploring drug resistance in HIV-1 proteases

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.