GABA-A Receptor Allosteric Modulator

Target Identification

GABA-A receptors are the primary inhibitory neurotransmitter receptors in the central nervous system. Dysregulation of GABAergic signaling is implicated in anxiety disorders, epilepsy, and insomnia. Our program focuses on developing subtype-selective allosteric modulators with improved safety profiles.

Approach

Our computational approach combines:

• Receptor modeling: Homology modeling of GABA-A receptor subtypes
• Binding site analysis: Identification of allosteric binding pockets
• Virtual screening: Docking-based screening of focused compound libraries
• Selectivity prediction: Machine learning models for subtype selectivity

Current Status

The program is in the lead stage with promising compounds showing subtype selectivity for alpha2/alpha3-containing GABA-A receptors, which are associated with anxiolytic effects without sedation.

Key Milestones

• Target validation: Confirmed alpha2/alpha3 subtype selectivity as therapeutic strategy
• Hit identification: Screening campaign identified 8 hit series
• Lead generation: Medicinal chemistry optimization yielded lead series L-GA-23