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

Jianzhong Chen, Xingyu Wang, Tong Zhu, Qinggang Zhang, John Z.H. Zhang

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)1903-1913
Number of pages11
JournalJournal of Chemical Information and Modeling
Issue number9
StatePublished - Sep 28 2015


ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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