New Insights into the In Silico Prediction of HIV Protease Resistance to Nelfinavir

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.

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

“…The results of the free energy calculations are listed in Table , and we can see that three inhibitors show a significant decrease (>10 kcal/mol) in binding energy for the I36T↑T protease compared to the subtype B and wild‐type proteases. Although ATV shows a decrease in binding, it is not at the same magnitude as the three inhibitors IDV, NFV and TPV, which are the only non‐pepditic protease inhibitors in this group . On the other hand, RTV, APV and IDV shows improved calculated binding energies in comparison with the corresponding data for C‐SA PR.…”

Flap Dynamics in Aspartic Proteases: A Computational Perspective

“…Antunes et al . used several bioinformatics tools to understand the effect of D30V and V32E mutations on the dynamics of HIV‐PR‐nelfinavir complex. They found that V32E mutation tends to adapt an open conformation much more rapidly than the wild type and D30V apo HIV‐PR.…”

Exploring the conformational landscapes of HIV protease structural ensembles using principal component analysis

“…The search for permanent cure for HIV still continues. The HIV life cycle is vitally influenced by the activity of the viral protease that cleaves the Gag and Gag‐Pol viral polyproteins into structural and functional proteins essential for proper virion assembly and maturation . HIV‐1 protease exists as a symmetric homo‐dimer having 99 amino acids in each subunit .…”

“…The HIV life cycle is vitally influenced by the activity of the viral protease that cleaves the Gag and Gag‐Pol viral polyproteins into structural and functional proteins essential for proper virion assembly and maturation . HIV‐1 protease exists as a symmetric homo‐dimer having 99 amino acids in each subunit . The substrate accesses the protease active site through the flap region of the homo‐dimer that shifts from open to closed conformation to bind and thereby cleave the substrate …”

“…HIV‐1 protease exists as a symmetric homo‐dimer having 99 amino acids in each subunit . The substrate accesses the protease active site through the flap region of the homo‐dimer that shifts from open to closed conformation to bind and thereby cleave the substrate …”