I n-silico drug repurposing for lysyl oxidase inhibition and ferroptosis prevention in epilepsy.

Abstract

Epilepsy represents a prevalent symptom across various neurological disorders, which is characterized by the abnormal firing of neurons from diverse brain regions, resulting in impulsive frequent seizures, protracted seizures can cause cell death and neuronal damage. Ferroptosis, recently acknowledged as a regulated form of cell death, involves the excessive deposition of iron ions culminating in the build-up of harmful lipid-based reactive oxygen species. Some recent research findings have suggested that lysyl oxidase (LysOx) depicts a vital role in the development of various neurological diseases, yet the precise mechanism behind it is still not obscure. This study is done to study the mechanism of how LysOX leads to ferroptosis leading to epileptogenesis. We have screened compounds from FDA-approved libraries, and molecules with top docking scores were selected. Pharmacokinetic property, mainly its capability to permeate the blood-brain barrier is important for therapeutic compounds. In this extensive study, we executed virtual screening using an in-silico approach to identify a novel therapeutic compound, capable of targeting LysOX. We used an FDA-approved library to analyze the capability of ligands with LysOX. furthermore, ADMET was also performed (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling, and molecular dynamics simulations, to identify the most capable compounds. Our elaborate computational study uncovered a set of highly encouraging compounds. These compounds showed great results in inhibiting LysOX and preventing the ferroptotic cell death mechanism which leads to epilepsy.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00373-x.