In-Silico Drug Repurposing of 6-(2,2,3,3-Tetrafluoropropoxy)-1,3-Benzothiazole-2-Amine Targeting Voltage-Gated Sodium Channels in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a severe and progressive neurodegenerative disorder marked by the selective loss of upper and lower motor neurons. Increasing evidence indicates that altered neuronal excitability, driven in part by dysfunction of voltage-gated sodium channels, contributes significantly to disease progression by promoting excessive sodium influx and subsequent neuronal injury. Current pharmacological options, including riluzole, offer only modest clinical benefit, underscoring the need for alternative therapeutic strategies.
In the present study, a ligand-based drug repurposing approach was applied to identify potential modulators of voltage-gated sodium channels for ALS management. Drug-like compounds were initially screened using Morgan fingerprint-based similarity analysis, followed by structure-based molecular docking using the CB-Dock platform to assess binding interactions with the sodium channel target. Among the evaluated compounds, 6-(2,2,3,3-tetrafluoropropoxy)-1,3-benzothiazole-2-amine exhibited a higher binding affinity and a more favorable interaction profile than riluzole.Detailed interaction analysis indicated stable accommodation of the ligand within the channel cavity, supported by key hydrophobic contacts and hydrogen-bond interactions with functionally relevant residues. Molecular dynamics simulations further validated the structural stability of the ligand–protein complex over the simulation period. Additionally, in silico ADMET and toxicity assessments suggested acceptable drug-likeness and safety properties.
Collectively, these findings indicate that 6-(2,2,3,3-tetrafluoropropoxy)-1,3-benzothiazole-2-amine represents a promising repurposed candidate for targeting voltage-gated sodium channels in ALS. This study demonstrates the utility of computational drug repurposing strategies in identifying potential therapeutic agents for neurodegenerative disorders.