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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
Author(s) -
Ahmed Shaimaa M.,
Maguire Glenn E. M.,
Kruger Hendrik G.,
Govender Thirumala
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12262
Subject(s) - saquinavir , indinavir , nelfinavir , molecular dynamics , mutant , chemistry , hiv 1 protease , drug , stereochemistry , active site , drug resistance , wild type , binding site , protease , autodock , human immunodeficiency virus (hiv) , biochemistry , biology , virology , pharmacology , genetics , computational chemistry , enzyme , gene , sida , viral disease , viral load , antiretroviral therapy , in silico
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 ), V 82 A and V 82 F /I84 V 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 V 82 F /I84 V variant, saquinavir, indinavir, and nelfinavir lose remarkable entropic contributions relative to both wild‐type and V 82A C ‐ SA HIV PR s. 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.