Novel Anti-Epileptic Drug Design Targeting the Brain Capillary Leakage Pathway; An in silico Approach

Background and Objective: Cytosolic phospholipase A2 (cPLA2), an important isoform of PLA2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of Epileptic seizures through mediation of brain capillary leakage.The expression and activation of cPLA2 are significantly higher in epilepsy.Novel strategies are needed to substantially reverse the effect of cPLA2 activation.To identify a new lead molecule that can serve as a baseline for developing a new drug for refractory epilepsy. Methodology:In this research project, in silico approach was used to identify lead compounds to be developed into marketable drugs with further SAR studies.While 164 compounds with potential cPLA2 inhibitory activity, including phytochemicals from the plant Centella asiatica, were selected and downloaded from the PubChem database.These compounds were docked against a 3D model of the enzyme cPLA2 using the CLC Drug Discovery Workbench.Those with docking scores higher than that of the known inhibitor ATK were chosen to be screened using PreADMET server.The compound with the most favorable ADME, drug-likeness and toxicity profile was chosen for the next phase of drug development i.e., SAR studies.Results: A total of 164 compounds were screened for their docking affinity using CLC drug discovery Workbench.Of those, 23 compounds were found to have higher docking results than the known inhibitor ATK.Those 23 compounds underwent PreADMET screening and the compound with PubChem CID 9826222 and IUPAC name 2-[2-[4-(5-phenylpentylsulfanyl) phenoxy] acetyl]-1, 3-benzoxazole-5carboxylic acid with a very high docking score of -62.74, was chosen for its favorable ADME, drug-likeness and toxicity profiles. Conclusion:The identified potential drug candidate can serve as a lead compound for further SAR modifications as well as in vitro and in vivo studies.