A novel pharmacophore model to identify leads for simultaneous inhibition of anti-coagulation and anti-inflammatory activities of snake venom phospholipase A(2)

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.).