Molecular alteration in drug susceptibility against subtype B and C-SA HIV-1 proteases: MD study

Abstract

HIV-1 protease (HIV PR) is one of the most promising targets for anti-HIV drug discovery. Extensive anti-HIV drug discovery research was focused on HIV-1 subtype B protease though FDA-approved protease inhibitors (PIs) generally exhibit altered biological activities against other protease subtypes such as South African subtype C (C-SA) protease that is prevalent in sub-Saharan Africa. Recent experimental reports highlight the differences in dynamic behaviors between these two protease subtypes. Herein, the dynamics of three FDA approved PIs, namely atazanavir (ATV), darunavir (DRV), and ritonavir (RTV), were thoroughly analyzed for both subtypes B and C protease complexes using molecular dynamic (MD) simulation in explicit solvent. The comparative MD post-analyses through flap dynamics, cross-correlation analyses, principal component analyses (PCA), per residue decomposition analyses, and MM-GBSA binding free energy analyses, revealed the altered responses observed in the complexes of these PIs in these two protease subtypes. The calculated theoretical binding energy analyses are consistent with the experiment to a considerable extent. Theoretical binding energies combined with flap dynamics appear to correspond to altered drug susceptibility against subtype B and C-SA HIV-1 proteases. The current analyses provide useful insight on the mechanism of action of PIs against these two different HIV-1 protease subtypes which will be helpful in developing new anti-protease compounds.