Molecular dynamics simulations exploring drug resistance in HIV-1 proteases |
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Authors: | Hui Gu HaiFeng Chen DongQing Wei JingFang Wang |
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Affiliation: | GU Hui, CHEN HaiFeng, WEI DongQing & WANG JingFang |
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Abstract: | 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 an-tiretroviral 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. |
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Keywords: | HIV-1 protease drug resistance hydrophobic interactions hydrogen bonds molecular dynamics simulations |
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