Bioactive fungal compounds as potential anti-HIV agents against HIV-1 protease: a multi-faceted molecular modelling approach for drug discovery

HIV-PR is a prominent pharmacological target that is driving the development of various possible HIV inhibitors. Unfortunately, the viral strain population has evolved to be even more resistant to medications; therefore, studying the dynamic structures of both WT and mutant viruses, besides their interactions with inhibitors, may be advantageous. Molecular dynamics analyses and free-energy calculations on the WT and four important resistance mutants (V82F, I84V, I50V, and V82F/I84V) of HIV-PR complexed with fungal compounds were performed to completely examine the mechanism of HIV-PR drug resistance. To determine precise binding free energies, we utilized an MM/GBSA method based on molecular mechanics. In this study, we found that compared to WT and single mutants, the double mutant (V82F/I84V) exhibited less flexibility and less curling of the flap tips. Contradiction with prior studies, our data reveal that the double mutant (V82F/I84V) facilitates binding affinity, suggesting that this variant may be particularly well suited to Ganomycin-I. The energy decomposition study shows that an increase in E_vdw energy by 6.56 kcal/mol is responsible for much of the increased binding observed for the double mutant (V82F/I84V) HIV-PR, which plays a direct role in increasing the binding affinity by approximately -1.62 (Val82' to Phe82') and -1.08 (Ile84' to Val84') kcal/mol, accounts for 41% of the total gain of the binding affinity. In addition to the direct impacts of Phe82' and Val84', the residues Gly27, Ala28, Asp29, Asp30, Ile47, and Ile50 each contribute more than -1 kcal/mol to the enhanced binding affinity of (V82F/I84V) HIV-PR towards the inhibitor.