Discovering novel inhibitors of P2Y12 receptor using structure-based virtual screening, molecular dynamics simulation and MMPBSA approaches

Abstract

P2Y12, a G-protein coupled receptor is involved in platelets plug formation and it amplifies and maintains the process of platelet aggregation. P2Y12 is considered as a potent target to inhibit platelet aggregation in thrombotic and cardiac emergencies. This research focuses on in silico inhibition of P2Y12 by structure-based drug design techniques. Initially, drug-like compounds were selected from ZINC database by structure-based pharmacophore model. Subsequently, 4479 compounds matched with the pharmacophore model that were scrutinized by molecular docking. Later, based on docking score and rank, top 10% of the docked library was selected to predict their pharmacokinetic properties and 191 compounds possessed good pharmacokinetic profile. The binding pattern of those compounds were analyzed to select novel, less toxic and more potent P2Y12 antagonists. In protein-ligand interaction analysis, seven compounds showed significant binding potential, therefore examined through molecular dynamic simulation. Among the selected hits, two compounds (CP31 and CP32) exhibited higher binding energies in SANDER Poisson-Boltzmann Surface Area (PBSA) approach than agonist bound P2Y12 (4PXZ) and antithrombotic drug bound P2Y12 (4NTJ), while one compound (CP25) showed comparable binding energy than 4NTJ. The binding free energy analysis reflect that interactions of all selected Hits with P2Y12 are promising and specifically CP25, CP31, and CP32 could serve as novel inhibitors of P2Y12.