Drug repositioning for idiopathic epilepsy using gene expression signature data

Area of Science:

• Neurology
• Pharmacology
• Bioinformatics

Background:

• Epilepsy is a common neurological disorder with a significant burden, and 30-40% of patients have drug-resistant epilepsy.
• Genetic or idiopathic epilepsy accounts for 40% of cases, highlighting the need for novel treatment strategies.

Purpose of the Study:

• To conduct a gene expression-based drug repositioning study for epilepsy.
• To identify potential drug candidates for treating drug-resistant and idiopathic epilepsy.

Main Methods:

• Retrieved epilepsy gene expression data from the Gene Expression Omnibus database.
• Utilized the Connectivity Map (CMAP) for drug-associated gene expression data.
• Employed an R-script to predict 309 drug compounds targeting epilepsy gene signatures.
• Performed molecular docking against key epilepsy targets: Voltage-gated sodium channel subunit α2 (Nav1.2), GABA receptor α1-β1, and Voltage-gated calcium channel α1G (Cav3.1).

Main Results:

• Predicted 309 drug compounds capable of altering epilepsy-related gene expression signatures.
• Identified 21 drug compounds demonstrating superior binding affinity to epilepsy targets compared to standard drugs (Carbamazepine, Clonazepam, Pregabalin).
• Highlighted Ergocalciferol, Oxaprozin, Flunarizine, Triprolidine, and Cyproheptadine as promising candidates with previously reported anti-epileptic activities.

Conclusions:

• Gene expression-based drug repositioning is a viable strategy for identifying novel epilepsy treatments.
• Several repurposed drug compounds show potential for targeting idiopathic and drug-resistant epilepsy.
• Further investigation of identified compounds like Ergocalciferol, Oxaprozin, Flunarizine, Triprolidine, and Cyproheptadine is warranted for clinical application.