Virtual analysis of structurally diverse synthetic analogs as inhibitors of snake venom secretory phospholipase A2

Due to the toxic pathophysiological role of snake venom phospholipase A(2) (PLA(2)), its compelling limitations to antivenom therapy in humans and the need for alternative therapy foster considerable pharmacological interest towards search of PLA(2) 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 A(2) fraction-V) belonging to Group II-B secretory PLA(2) 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 PLA(2) whose selection is based on IC50 value that ranges from 25 mu M to 100 mu M. 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 PLA(2) recognition and anti-ophidian activity. Copyright (C) 2015 John Wiley & Sons, Ltd.