The Impact of Active Site Mutations of South African HIV PR on Drug Resistance: Insight from Molecular Dynamics Simulations, Binding Free Energy and Per-Residue Footprints

• Published in: Chemical biology & drug design 2014-04, Vol.83 (4), p.472-481
• Main Authors: Ahmed, Shaimaa M., Maguire, Glenn E. M., Kruger, Hendrik G., Govender, Thirumala
• Format: Article
• Language: English
• Subjects: Africa; binding free energy calculations; Catalytic Domain; Drug Resistance, Viral - drug effects; HIV Protease - genetics; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV protease subtype C; molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Mutation; Thermodynamics
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12262

Molecular dynamics simulations and binding free energy calculations were used to provide an understanding of the impact of active site drug‐resistant mutations of the South African HIV protease subtype C (C‐SA HIV PR), V82A and V82F/I84V on drug resistance. Unique per‐residue interaction energy ‘footprints’ were developed to map the overall drug‐binding profiles for the wild type and mutants. Results confirmed that these mutations altered the overall binding landscape of the amino acid residues not only in the active site region but also in the flaps as well. Four FDA‐approved drugs were investigated in this study; these include ritonavir (RTV), saquinavir (SQV), indinavir (IDV), and nelfinavir (NFV). Computational results compared against experimental findings were found to be complementary. Against the V82F/I84V variant, saquinavir, indinavir, and nelfinavir lose remarkable entropic contributions relative to both wild‐type and V82A C‐SA HIV PRs. The per‐residue energy ‘footprints’ and the analysis of ligand–receptor interactions for the drug complexes with the wild type and mutants have also highlighted the nature of drug interactions. The data presented in this study will prove useful in the design of more potent inhibitors effective against drug‐resistant HIV strains. Molecular dynamics and binding free energy calculations showed that the binding affinity of inhibitors for the V82F/I84V double mutant is impaired significantly compared with wild type and V82A mutant. It was found that localized mutations can disturb the binding affinity of the inhibitors toward the nearby, and some cases distant, residues. Entropic loss was found to play a role in binding affinity with some inhibitors more than the others.