Multi-Target Approach for Drug-Resistant Epilepsy: An In Silico Exploration of Promising Phytochemicals

The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway, involving NLRP3 protein and caspase-1, is reported to be involved in the progression of epilepsy into drug-resistant epilepsy (DRE). Overactivation of ABC transporter proteins in neuronal cells as a result of NLRP3 activation leads to the efflux of the anti-seizure medications, rendering them ineffective. This work aims to identify novel hit molecules that can halt neuroinflammation as well as potentiate the action of anti-seizure medications. Initially, molecular docking studies evaluated procyanidin binding against NLRP3, caspase-1, and ABC proteins as -177.001, -126.842, and -143.671. Procyanidin was further subjected to MD simulations for 100 ns, revealing RMSD values below 5 Å for procyanidin in complex with ABC and caspase proteins, whereas with NLRP3, it was below 2.5 Å. Procyanidin showed a ΔG binding value of -82.10142857 ± 15.07 with caspase, -61.9005 ± 9.95 with NLRP3, and -101.021 ± 5.27 kcal/mol with ABC protein. Procyanidin was predicted to bear good plasma-protein binding and a class 5 acute toxicity class ligand. It also showed a band energy gap of -4.873 eV, which suggested its stability.