Identification of chemically diverse GABA agonists as potential anti-epileptic agents using structure-guided virtual screening, ADMET, quantum mechanics and clinical validation through off-target analysis.

Development of resistance against existing anti-epileptic drugs has alarmed the scientific innovators to find novel potential chemical starting points for the treatment of epilepsy and GABA inhibition is a promising drug target strategy against epilepsy. The crystal structure of a subtype-selective β3-homopentameric ligand-gated ion channel of GABA receptor has been used for the first time for screening the Asinex library for discovery of GABA agonists as potential anti-epileptic agents. Co-crystallized ligand established the involvement of part of the β7-β8 loop (Glu155 and Tyr157) and β9-β10 loop (Phe200 and Tyr205) residues as the crucial amino acids in effective binding, an essential feature, being hydrogen bond or ionic interaction with Glu155 residue. Top ranked hits were further subjected to binding energy estimation, ADMET analysis and ligand efficiency matric calculations as consecutive filters. About 19 compounds qualifying all parameters possessed interaction of one positively charged group with Glu155 with good CNS drug-like properties. Simulation studies were performed on the apo protein, its complex with co-crystallized ligand and the best hit qualifying all screening parameters. The best hit was also analyzed using Quantum mechanical studies, off-target analysis and hit modification. The off-target analysis emphasized that these agents did not have any other predicted side-effects.