High-affinity selective inhibitor against phospholipase A₂ (PLA₂): a computational study

Abstract

Phospholipase A₂ (PLA₂) is the most abundant protein found in snake venom. PLA₂ induces a variety of pharmacological effects such as neurotoxicity, myotoxicity and cardiotoxicity as well as anticoagulant, hemolytic, anti-platelet, hypertensive, hemorrhagic and edema inducing effects. In this study, the three dimensional structure of PLA₂ of Naja sputatrix (Malayan spitting cobra) was modeled by I-TASSER, SWISS-MODEL, PRIME and MODELLER programs. The best model was selected based on overall stereo-chemical quality. Further, molecular dynamics simulation was performed to know the stability of the modeled protein using Gromacs software. Average structure was generated during the simulation period of 10 ns. High throughput virtual screening was employed through different databases (Asinex, Hit finder, Maybridge, TOSLab and ZINC databases) against PLA₂. The top seven compounds were selected based on the docking score and free energy binding calculations. These compounds were analyzed by quantum polarized ligand docking, induced fit docking and density functional theory calculation. Furthermore, the stability of lead molecules in the active site of PLA₂ was employed by MD simulation. The results show that selected lead molecules were highly stable in the active site of PLA₂.

• IFD
• MD simulation
• molecular modeling
• PLA₂
• QPLD

Acknowledgements

The authors gratefully acknowledge the infrastructure facilities provided by the Department of Bioinformatics, Alagappa University, Post Graduate Diploma in Structural Pharmacogenomics.

Declaration of interest

This work was funded by UGC, Government of India. No. F.14-13/2013 (Inno/ASIST) dated 30.03.2013.