In Silico drug repurposing pipeline using deep learning and structure based approaches in epilepsy

Abstract

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.

Keywords

• Drug repurposing
• Epilepsy
• Gain-of-function gene
• Docking
• Deep learning
• BBB (blood–brain barrier) permeability