Computational drug repositioning approach to predict first-line therapeutics for epilepsy

Epilepsy affects millions of people globally, with approximately one-third of patients experiencing drug-resistant seizures. Developing new anti-epileptic drugs is time-intensive and costly, prompting interest in computational drug repositioning strategies. Here we report about a comprehensive drug repositioning approach to identify the first-line therapeutic option(s) for epileptic seizures. All approved drugs from the DrugBank database were screened for their anti-epileptic properties that involved their blood brain permeability prediction and clustering them for structural similarity with the marketed anti-epilepsy drugs. The screened drugs were subjected to molecular docking against previously identified therapeutic target proteins (Voltage-Gated Sodium Channel α2; GABA receptor α1-β1; and Voltage-Gated Calcium Channel α1G), A total of 46 drugs showed better binding affinity than the respective standard drugs - Carbamazepine, Clonazepam and Pregabalin for the selected target proteins - Voltage-Gated Sodium Channel α2; GABA receptor α1-β1; and Voltage-Gated Calcium Channel α1G, respectively. The binding pocket and literature data mining revealed three drugs, Oxaprozin, Pizotifen, and Cyproheptadine, that bind within the precise binding pocket and have no reported severe side effects related to seizure onset. The molecular dynamic simulation studies showed all three compounds with better and more stable binding interactions against the corresponding drug targets. Oxaprozin, among identified 3 drugs, showed a very stable binding and can be a considered a potential repurposed drug against epilepsy, inviting further pre-clinical trials.