Identification of Novel Potential gp120 of HIV-1 Antagonist Using Per-Residue Energy Contribution-Based Pharmacophore modelling.

Inhibition of HIV-1 target cell entry, by targeting gp120, has been identified as a promising approach for the identification and development of prophylactic and salvage HIV infection inhibitors. A small molecule compound 18A is an important chemotype in the development of novel and diverse viral cell entry inhibitors, as it inhibits a wide variety of HIV strains by disrupting allosteric structuring on gp120. This study combines residue energy contribution (REC) pharmacophore mapping of 18A and in silico molecular docking in a virtual screening campaign to identify novel and diverse antagonists of gp120. The binding free energy of a validated docked complex of gp120-18A and the quantitative contribution of interacting residues were obtained with a more accurate molecular mechanics/generalised born surface area (MM/GBSA) method followed by mapping the energetically favourable residue contributions onto atom centres in 18A to obtain a pharmacophore model. The generated pharmacophore hypothesis was used to search the ZINC database for 3D structures that match the pharmacophore. Further, molecular docking, molecular dynamics simulations and binding free energy analysis were performed on retrieved hits in order to rank hits based on their affinity and interactions in the CD4 binding cavity of a gp120. Interestingly, the top scoring compound designated with ZINC database ID as ZINC64700951 (docking score = -8.8 kcal/mol, ∆G = -43.77 kcal/mol) showed higher affinity compared to compound 18A docking score = -7.3 kcal/mol, ∆G = -31.97 kcal/mol) and interaction of ZN64700951 with validated allosteric hot spot residues, Asp368 and Met426, and binding hot spot residues, Asn425, Glu370, Gly473, Trp427 and Met475 in gp120, suggest that ZN64700951 is a promising antagonist of gp120. Thus, ZN64700951 could serve as an additional prototype for further optimisation as an HIV target cell viral entry inhibitor.