Virtual screening and molecular fingerprinting for <i>in silico</i> designing of potential CCR5 inhibitors targeting HIV therapy

The CC chemokine receptor 5 (CCR5) is the principal entry receptor for HIV1 (macrophage tropic) as observed in the early stages of viral replication during attachment to the host cell. The coreceptor switch is one of the possible mechanisms for viral resistance. Hence, molecules designed to bind and inhibit CCR5 or CXCR4 would be effective in HIV (human immunodeficiency virus) therapy to prevent entry of the virus, stop further infection of cells, and allow time for its clearance from the body (through immunity intervention). The aim of this study was to design effective and safer CCR5 coreceptor antagonists. Two ligand-based pharmacophore models were generated with drugs in market and clinical trials using PharmGist tool. The model was utilized to screen the ZINC database to obtain compounds with the required features and proceed for docking with AutoDock tools. Top ten compounds with good docking score and significant interactions at the active pocket were advanced to ADME (absorption, distribution, metabolism, and excretion) and toxicity predictions. Interestingly, ZINC08948076 (Mol1) and ZINC08966180 (Mol2) share similar molecular fingerprints with the drug molecule, BMS-813160. In contrast, the MD simulation trajectories revealed ZINC13150285 (Mol3) and maraviroc to have similar conformational dynamics (RMSD and Rg) between the ligand and the target protein. Additionally, ZINC24968598 (Mol4) was observed to have the lowest potential energy and ZINC09515758 (Mol5) with the lowest interaction energy. Overall, the study could identify ZINC09515758 and ZINC00673808 as potential hit molecules for further experimental investigation.