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

Received 07 Jan, 2024

Accepted 09 Nov, 2024

Published 01 Jan, 2025

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-5-carboxylic 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.

KEY CONTRIBUTIONS

	•	The identified compound showed a very good docking score of -62.74 which is even higher than that of the known cPLA2 inhibitor arachidonyl trifluoromethyl ketone (ATK) (with PubChem CID 5280436) which showed a docking score of -61.7
	•	The compound is non-mutagenic, non-carcinogenic in both mouse and rats and a low risk hERG inhibitor which is superior to that of ATK (non-mutagenic but carcinogenic in both rodents and a medium hERG inhibition)
	•	We recommend considering the compound with PubChem CID 9826222 and IUPAC name 2-[2-[4-(5-phenylpentylsulfanyl) phenoxy] acetyl]-1, 3-benzoxazole-5-carboxylic acid for further SAR modification as well as in vitro and in vivo studies

FUTURE DIRECTIONS

There is an imminent need for the development of a novel AED to tackle the ever increasing cases of refractory epilepsy. The above mentioned theories regarding the leaky BBB and the role of cPLA2 in epileptogenesis make the enzyme cPLA2 an excellent target for therapeutic intervention of refractory epilepsy.

ACKNOWLEDGMENTS

We express our heartiest and sincere gratitude to Dr. Yemane Seyoum, Dean Orotta College of Medicine And Health Sciences (OCMHS) and Mr. Elias Teages, Director of student affairs at OCMHS for requesting the assistance of WHO office in providing us with access to fast internet connection.