Pharmacophore-based identification and molecular docking of CCR5 inhibitors: insights from dynamic simulations
Abstract The chemokine receptor type 5 (CCR5) plays a crucial role in HIV-1 entry into host cells, making it a key therapeutic target. This study aimed to identify novel CCR5 inhibitors through pharmacophore-guided virtual screening and molecular dynamics (MD) simulations using ZINC-derived compounds. The 3D structure of CCR5 (PDB ID: 4MBS) was used as the target receptor. A ligand-based pharmacophore model was generated using the Pharmit server, with Maraviroc as a reference molecule. Virtual screening of ZINC compounds was conducted based on pharmacophore features and Lipinski’s Rule of Five. The top 10 compounds were subjected to molecular docking, ADMET analysis, and MD simulations using GROMACS to evaluate stability and binding dynamics. Among all screened ligands, ZINC000000867238 exhibited the strongest binding affinity (–10.0 kcal/mol), forming hydrogen bonds with Tyr251 and Glu283, and hydrophobic interactions with Trp86, Phe182, and Tyr108. The compound demonstrated favorable ADMET characteristics, including high absorption, non-mutagenicity, and absence of hERG inhibition. MD simulation confirmed its stability, with RMSD fluctuations between 0.20–0.38 nm, low RMSF deviations in active site residues, and a compact radius of gyration (∼2.48 nm) compared to apo-CCR5. The integrated computational approach identified ZINC000000867238 as a potent and stable CCR5 inhibitor candidate, warranting further in vitro and in vivo validation as a potential HIV-1 entry blocker.