Molecular dynamics and free energy studies on the wild-type and mutated hiv-1 protease complexed with four approved drugs: Mechanism of binding and drug resistance

Stefano Alcaro, Anna Artese, Francesca Ceccherini-Silberstein, Francesco Ortuso, Carlo Federico Perno, Tobias Sing, Valentina Svicher

Research output: Contribution to journalArticle


The current strategy to improve the quality of life of Human Immunodeficiency Virus (HIV) infected individuals through suppressing viral replication and maintaining the virus at low to undetectable levels is based on highly active antiretroviral therapy (HAART). Protease inhibitors are essential components of most HAART protocols and are often used as the first line of treatment. However, a considerable percentage of new HIV-1 infections are caused by viruses carrying antiretroviral drug-resistant mutations. In this paper molecular dynamics, docking simulations, and free energy analysis of mutated HIV protease complexes were used to estimate the influence of different drug resistance-associated mutations in lopinavir, amprenavir, saquinavir, and atazanavir protease recognition. In agreement with virological and clinical data, the structural analysis showed that the single mutations V82A, I84V, and M46I are associated with higher energetic values for all analyzed complexes with respect to wild-type, indicating their decreased stability. Interestingly, in atazanavir complexes, in the presence of the L76V substitution, the drug revealed a more productive binding affinity, in agreement with hypersusceptibility data.

Original languageEnglish
Pages (from-to)1751-1761
Number of pages11
JournalJournal of Chemical Information and Modeling
Issue number7
Publication statusPublished - Jul 27 2009


ASJC Scopus subject areas

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

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