Discovery of a new Daboia russelli viper venom PLA2 inhibitor using virtual screening of pharmacophoric features of co-crystallized compound

Snake venom PLA(2), a member of the group of hydrolase enzymes, has been recognized as a promising drug target for snake envenomation. In the present study, an attempt was made to identify potential inhibitors of snake venom PLA(2) by employing a pharmacophore-based virtual screening, docking, and dynamics approach. A receptor-based pharmacophore model was generated based on the features of the established and bound co-crystal ligand (2-carbamoylmethyl-5-propyl-octahydro-indol-7-yl)-acetic acid in the PLA(2) complex. The best pharmacophore model (ADDH) derived, consisted of four features, namely one hydrogen bond acceptor, two hydrogen bond donors, and one hydrophobic region. This common pharmacophore was then used to perform virtual screening against a drug-like diverse database, with due consideration to the Lipinski 'rule of five', so as to obtain a pool of lead molecules. The short-listed lead molecules were then subjected to docking analysis with that of the Daboia russelli viper venom PLA(2) followed by a molecular simulation study for a duration of 100 ns. CAP04815700 was chosen as the best compound based on the simulation parameters, which were then taken for MM/PBSA calculation, and it was revealed that it has a similar effective inhibitory potential as that of the crystal ligand. Further, the cluster analysis also revealed the structural significance of the backbone protein after the interaction with CAP04815700. This study will continue to explore its bioactivity in vitro and in vivo.Communicated by Ramaswamy H. Sarma

Automated summary

In this study, potential inhibitors of snake venom PLA(2) were identified through pharmacophore-based virtual screening, docking, and dynamics approach. The best pharmacophore model consisted of one hydrogen bond acceptor, two hydrogen bond donors, and one hydrophobic region. CAP04815700 was found to have similar inhibitory potential as the crystal ligand, and further investigation of its bioactivity will be conducted in vitro and in vivo.