An integrated approach in the search of GABA aminotransferase inhibitors
Savita Bhutoria, firstname.lastname@example.org and Nanda Ghoshal, email@example.com, Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Jadavpur, kolkata, India
gamma aminobutyric acid is the inhibitory neurotransmitter in the mammalian central nervous system. The major pathway for its degradation involves the pyridoxal phosphate (PLP) dependent enzyme, GABA aminotransferase (GABA-AT). Designing GABA-AT inhibitors is trivial task, first because of very small enzyme active site and second the inhibitor should first react with PLP for enzyme inactivation. The inhibitors can attack the enzyme reversibly and irreversibly depending on the fact that inhibitor binds to only PLP or with PLP and protein. The solution applied here involved a set of multiple approaches together for designing new inhibitors. Using a virtual library, created by LUDI based fragments, substructures and subsequent isosteric group replacement, molecules were screened with structure guided multiple pharmacophores having the reversible and irreversible attacking functionalities. A set of similarity assessment methods and clustering was employed to recommend compounds for screening in a prospective docking experiment. The inhibitors should first react with the PLP and then with the enzyme, so a strategy was used in which hits were analyzed and validated by their tendency to react with PLP and formation of ternary complex. The hits selected were further evaluated and prioritized using QSAR analysis, which included the shape of the molecule into account and other important electronic and structural attributes of the molecules. Thus here a combined virtual screening and QSAR methodology is used to target the GABA-AT enzyme, reversibly and irreversibly. The new actives contained different underlying chemical architecture to the known inhibitors, results indicative of successful scaffold-hopping.