A Novel Pharmacophore Model to Identify Leads for Simultaneous Inhibition of Anti‐coagulation and Anti‐inflammatory Activities of Snake Venom Phospholipase A2

Abstract

In addition to catalytic action, snake venom phospholipase A(2) induces several pharmacological effects including neurotoxicity, cardiotoxicity as well as anti-coagulant and anti-platelet aggregation effects. Therefore, strategy to identify dual inhibitor for this enzyme will be of much importance in medical research. In this paper, structure-based pharmacophore mapping, molecular docking, protein-ligand interaction fingerprints, binding energy calculations, and binding affinity predictions were employed in a virtual screening strategy to identify new hits for dual inhibition of anti-coagulation and inflammation of phospholipase A(2) . A structure-based pharmacophore map was modeled which comprised of important interactions as observed in co-crystal of phospholipase A(2) and its dual inhibitor indomethacin. The generated model was used to retrieve molecules from ChemBridge, a free database of commercially available compounds. A total of 381 molecules mapped on the developed pharmacophore model from ChemBridge database. The hits retrieved were further screened by molecular docking, protein-ligand interaction fingerprints, binding energy calculations, and binding affinity predictions using Genetic Optimization for Ligand Docking and moe. Based on these results, 32 chemo-types molecules were predicted as potential lead scaffolds for developing novel, potent and structurally diverse dual inhibitor of phospholipase A(2.).