title: A Comparative Insight into Amprenavir Resistance of Mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 Protease Based on Thermodynamic Integration and MM-PBSA Methods.
abstract: Drug resistance of mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 protease (PR) was found in clinical treatment of HIV patients with the drug amprenavir (APV). In order to elucidate the molecular mechanism of drug resistance associated with these mutations, the thermodynamic integration (TI) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods were applied to calculate binding free energies of APV to wild-type PR and these mutated PRs. The relative binding free energy differences from the TI calculations reveal that the decrease in van der Waals interactions of APV with mutated PRs relative to the wild-type PR mainly drives the drug resistance. This result is in good agreement with the previous experimental results and is also consistent with the results from MM-PBSA calculations. Analyses based on molecular dynamics trajectories show that these mutations can adjust the shape and conformation of the binding pocket, which provides main contributions to the decrease in the van der Waals interactions of APV with mutated PRs. The present study could provide important guidance for the design of new potent inhibitors that could alleviate drug resistance of PR due to mutations.
authors: School of Science, Shandong Jiaotong University , Jinan 250357 China.
authors: Jianzhong
authors: J
authors: Chen
authors: NYU-ECNU Center for Computational Chemistry at NYU Shanghai , Shanghai 200062, China.
authors: Xingyu
authors: X
authors: Wang
authors: State Key Laboratory of Precision Spectroscopy, Institute of Theoretical and Computational Science, East China Normal University , Shanghai 200062, China.
authors: Tong
authors: T
authors: Zhu
authors: Collage of Physics and Electronic Science, Shandong Normal University , Jinan 250014, China.
authors: Qinggang
authors: Q
authors: Zhang
authors: NYU-ECNU Center for Computational Chemistry at NYU Shanghai , Shanghai 200062, China.|State Key Laboratory of Precision Spectroscopy, Institute of Theoretical and Computational Science, East China Normal University , Shanghai 200062, China.
authors: John Z H
authors: JZ
authors: Zhang
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D005663:Furans; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D013449:Sulfonamides / Q000494:pharmacology; D013816:Thermodynamics; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D013449:Sulfonamides; D014764:Viral Proteins; C095108:amprenavir