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Abstract Due to considerable global prevalence and high recurrence rate, the pursuit of effective new medication for epilepsy treatment remains an urgent and significant challenge. Drug repurposing emerges as a cost-effective and efficient strategy to combat this disorder. This study leverages the transformer-based deep learning methods coupled with molecular binding affinity calculation to develop a novel in-silico drug repurposing pipeline for epilepsy. The number of candidate inhibitors against 24 target proteins encoded by gain-of-function genes implicated in epileptogenesis ranged from zero to several hundreds. Our pipeline has repurposed the medications with most anti-epileptic drugs and nearly half psychiatric medications, highlighting the effectiveness of our pipeline. Furthermore, Lomitapide, a cholesterol-lowering drug, first emerged as particularly noteworthy, exhibiting high binding affinity for 10 targets and verified by molecular dynamics simulation and mechanism analysis. These findings provided a novel perspective on therapeutic strategies for other central nervous system disease.