New insights into the in silico prediction of HIV protease resistance to nelfinavir

PLoS One. 2014 Jan 31;9(1):e87520. doi: 10.1371/journal.pone.0087520. eCollection 2014.

Abstract

The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy
  • Acquired Immunodeficiency Syndrome / enzymology
  • Acquired Immunodeficiency Syndrome / genetics
  • Amino Acid Substitution
  • Drug Resistance, Viral*
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease* / chemistry
  • HIV Protease* / genetics
  • HIV-1* / enzymology
  • HIV-1* / genetics
  • Humans
  • Mutation, Missense*
  • Nelfinavir / chemistry*

Substances

  • HIV Protease Inhibitors
  • HIV Protease
  • Nelfinavir

Grants and funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.