Identification of HIV-1 Entry Inhibitors through Ligand-Based Pharmacophore and Molecular Docking Analysis

Abstract

Background: In the global fight against HIV, the development of novel antiviral drugs targeting critical viral entry mechanisms remains a pressing need. This study aimed to identify potential CCR5 receptor inhibitors as promising candidates for anti-HIV drug discovery. From an initial pool of 122,276,899 compounds obtained from the ZINC database, Lipinski's rule of five was applied to filter for favorable pharmacokinetic properties, resulting in 52,272,894 ligands. A pharmacophore model was then generated using the standard drug Maraviroc. The generated pharmacophore model was used to screen the 52,272,894 ligands, yielding 38,402,967 compounds for further evaluation. Molecular docking simulations were performed using AutoDock 4.0 against the CCR5 receptor protein (PDB: 4MBS). The top 20 ligands were selected based on RMSD values and analyzed in detail. The results revealed that two compounds, ZINC000128130021 and ZINC000257322186, exhibited superior binding energies of -8.27 kcal/mol, surpassing the standard drug Maraviroc (-6.75 kcal/mol). These top compounds demonstrated extensive hydrogen bonding and hydrophobic interactions with key active site residues, as well as remarkably low inhibition constants of 871.63 nM and 862.99 nM, respectively, compared to Maraviroc (11.37 μM). The comprehensive screening and selection process, combined with the promising in silico results, suggest that ZINC000128130021 and ZINC000257322186 warrant further in vitro and in vivo evaluation as potential CCR5 receptor inhibitors with therapeutic potential for the treatment of HIV-1 infection