title: 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.).
authors.affiliation: Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.forename: Syed Abid
authors.initials: SA
authors.lastname: Ali
authors.forename: Rabia
authors.initials: R
authors.lastname: Sattar
authors.forename: Muhammad Arif
authors.initials: MA
authors.lastname: Lodhi
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors*; D000925:Anticoagulants / Q000037:antagonists & inhibitors*; D000931:Antidotes / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D008958:Models, Molecular; D064801:Phospholipase A2 Inhibitors; D012910:Snake Venoms / Q000201:enzymology*; D012911:Snakes / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D000931:Antidotes; D064801:Phospholipase A2 Inhibitors; D012910:Snake Venoms