title: In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies.
abstract: Snake venom, particularly of vipers from the Indian subcontinent, contains Phospholipase A2 (PLA2) as one its constituents which is widely implicated in hemorrhagic, cardiac arrest and death. Development of inhibitors of the protein can facilitate the weakening or annihilation of the venom toxicity and save many human lives. In the present communication, our studies relate to the design and development of structure-based ligands as inhibitors of PLA2 of Viper venom. The study involves the computational approach towards evaluating a library of molecules comprising of natural products, and synthetic molecules through docking studies on the venom protein PDB ID: 1OXL (a dimer, available in the literature). In silico experiments have resulted in the identification of several of them as PLA2 inhibitors. The inhibitory effect of PLA2 by these compounds is attributed to a great extent to their interaction with the residues Phe 46 and Val47 of chain B of the target protein and hence these two residues are identified as the key contributor for the said activity. In order to validate the in silico findings, a selected panel of compounds have been tested by in vitro and in vivo experiments against the venom, which has led to the observance of significant corroboration between the wet lab and in silico findings, validating thereby the in silico approach used in the present study.
authors.affiliation: Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.forename: Mohd Iqbal
authors.initials: MI
authors.lastname: Alam
authors.forename: Zabeer
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Asha
authors.initials: A
authors.lastname: Bhagat
authors.forename: Subhash Chander
authors.initials: SC
authors.lastname: Taneja
authors.forename: Ghulam Nabi
authors.initials: GN
authors.lastname: Qazi
authors.forename: Surrinder
authors.initials: S
authors.lastname: Koul
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000997:Antivenins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000737:chemistry / Q000378:metabolism; D017840:Daboia / Q000502:physiology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D012909:Snake Bites / Q000628:therapy; D013816:Thermodynamics; D014633:Valine / Q000737:chemistry / Q000378:metabolism; D014757:Viper Venoms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000201:enzymology*
chemical_list: D000997:Antivenins; D004791:Enzyme Inhibitors; D064801:Phospholipase A2 Inhibitors; D054852:Small Molecule Libraries; D014757:Viper Venoms; D010649:Phenylalanine; D054467:Phospholipases A2; D014633:Valine