title: Virtual analysis of structurally diverse synthetic analogs as inhibitors of snake venom secretory phospholipase A2.
abstract: Due to the toxic pathophysiological role of snake venom phospholipase A2 (PLA2 ), its compelling limitations to anti-venom therapy in humans and the need for alternative therapy foster considerable pharmacological interest towards search of PLA2 specific inhibitors. In this study, an integrated approach involving homology modeling, molecular dynamics and molecular docking studies on VRV-PL-V (Vipera russellii venom phospholipase A2 fraction-V) belonging to Group II-B secretory PLA2 from Daboia russelli pulchella is carried out in order to study the structure-based inhibitor design. The accuracy of the model was validated using multiple computational approaches. The molecular docking study of this protein was undertaken using different classes of experimentally proven, structurally diverse synthetic inhibitors of secretory PLA2 whose selection is based on IC50 value that ranges from 25 μM to 100 μM. Estimation of protein-ligand contacts by docking analysis sheds light on the importance of His 47 and Asp 48 within the VRV-PL-V binding pocket as key residue for hydrogen bond interaction with ligands. Our virtual analysis revealed that compounds with different scaffold binds to the same active site region. ADME analysis was also further performed to filter and identify the best potential specific inhibitor against VRV-PL-V. Additionally, the e-pharmacophore was generated for the best potential specific inhibitor against VRV-PL-V and reported here. The present study should therefore play a guiding role in the experimental design of VRV-PL-V inhibitors that may provide better therapeutic molecular models for PLA2 recognition and anti-ophidian activity.
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613401, India.
authors.forename: V
authors.initials: V
authors.lastname: Sivaramakrishnan
authors.affiliation: Cardiomyocyte Toxicity and Oncology Research Lab, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613401, India.
authors.forename: M
authors.initials: M
authors.lastname: Ilamathi
authors.affiliation: Department of Chemistry, National Institute of Technology (NIT), Hamirpur, 177 005, India.
authors.forename: K S
authors.initials: KS
authors.lastname: Ghosh
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, 570006, India.
authors.forename: S
authors.initials: S
authors.lastname: Sathish
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, 570006, India.
authors.forename: T V
authors.initials: TV
authors.lastname: Gowda
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore, 570006, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Vishwanath
authors.affiliation: Department of Chemistry, University of Mysore, Mysore, 570006, India.
authors.forename: K S
authors.initials: KS
authors.lastname: Rangappa
authors.affiliation: Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain University, Jakkasandra post, Ramanagara, 562112, India.
authors.forename: B L
authors.initials: BL
authors.lastname: Dhananjaya
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry*; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors*; D012910:Snake Venoms / Q000201:enzymology*; D040681:Structural Homology, Protein
chemical_list: D064801:Phospholipase A2 Inhibitors; D012910:Snake Venoms; D054497:Phospholipases A2, Secretory
keywords: Daboia russelli pulchella; anti-venom; benzyl phenyl benzoates; molecular docking; phospholipase A2; protein databank; snakebite