Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase.
The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally.
['Pinto|Andrea|A|', 'Tamborini|Lucia|L|', 'Pennacchietti|Eugenia|E|', 'Coluccia|Antonio|A|', 'Silvestri|Romano|R|', 'Cullia|Gregorio|G|', 'De Micheli|Carlo|C|', 'Conti|Paola|P|', 'De Biase|Daniela|D|']
D000612:4-Aminobutyrate Transaminase D000596:Amino Acids D000818:Animals D020134:Catalytic Domain D060326:Chemistry Techniques, Synthetic D004353:Drug Evaluation, Preclinical D004791:Enzyme Inhibitors D062105:Molecular Docking Simulation D013329:Structure-Activity Relationship
GABA 3-Br-isoxazoline docking GABA cyclic analogue PLP-dependent enzyme