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

Journal of Chemical Information and Modeling
Jianzhong ChenJohn Z H Zhang

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.

References

Mar 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·K von der Helm
Jul 26, 1996·The Journal of Biological Chemistry·S PazhanisamyD J Livingston
Jul 1, 1998·Annual Review of Biophysics and Biomolecular Structure·A Wlodawer, J Vondrasek
Jun 6, 2000·Advanced Drug Delivery Reviews·G C Williams, P J Sinko
Jul 18, 2001·Journal of the American Chemical Society·D A JuddC L Hill
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·W Wang, P A Kollman
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Mar 18, 2005·Journal of Medicinal Chemistry·Dominique L N G SurlerauxPiet B T P Wigerinck
Feb 8, 2006·Health & Social Care in the Community·Michele FosterCaroline Glendinning
Dec 11, 2007·The Journal of Chemical Physics·Thomas SteinbrecherDavid A Case
Jul 4, 2008·Journal of Molecular Biology·Fengling LiuIrene T Weber
Aug 19, 2008·The Journal of Physical Chemistry. B·Yun DingJohn Z H Zhang
Mar 26, 2009·The Journal of Chemical Physics·Li L DuanJohn Z H Zhang
Jul 28, 2010·Antimicrobial Agents and Chemotherapy·Soo-Yon RheeRobert W Shafer
Sep 29, 2011·Journal of Computational Chemistry·Beisi XuGuohui Li
Dec 1, 2011·The Journal of Physical Chemistry. B·Ya GaoYe Mei
Feb 9, 2012·Physical Chemistry Chemical Physics : PCCP·Tong ZhuJohn Z H Zhang

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Citations

Nov 16, 2016·Journal of Biomolecular Structure & Dynamics·Parthiban MarimuthuVigneshwaran Namasivayam
May 16, 2017·Biochemistry·Rajeswari Appadurai, Sanjib Senapati
Jun 2, 2017·Physical Chemistry Chemical Physics : PCCP·Lili DuanJohn Z H Zhang
Jan 26, 2018·Frontiers in Molecular Biosciences·Changhao WangRay Luo
Sep 23, 2018·Journal of Biomolecular Structure & Dynamics·Ammar MohseniSadegh Hasannia
Feb 1, 2020·Journal of Biomolecular Structure & Dynamics·Md Fulbabu SkParimal Kar
Apr 23, 2020·Future Medicinal Chemistry·Jurica NovakVladimir A Potemkin
Sep 18, 2020·Briefings in Bioinformatics·Yanqiang HanJinjin Li
Aug 27, 2019·Frontiers in Chemistry·Lili DuanJohn Z H Zhang
Apr 25, 2020·Frontiers in Molecular Biosciences·Muhammad Tahir KhanDong-Qing Wei
Nov 15, 2018·International Journal of Molecular Sciences·Guodong HuJihua Wang
May 12, 2020·ChemMedChem·André L C S NascimentoMarlus Chorilli
Mar 15, 2020·International Journal of Molecular Sciences·Guodong HuJihua Wang

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