title: Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin.
abstract: We have synthesized three analogues of 4-amino-5-fluorohexanoic acids as potential inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), which were designed to combine the potency of their shorter chain analogue, 4-amino-5-fluoropentanoic acid (AFPA), with the greater enzyme selectivity of the antiepileptic vigabatrin (Sabril®). Unexpectedly, these compounds failed to inactivate or inhibit the enzyme, even at high concentrations. On the basis of molecular modeling studies, we propose that the GABA-AT active site has an accessory binding pocket that accommodates the vinyl group of vigabatrin and the fluoromethyl group of AFPA, but is too narrow to support the extra width of the distal methyl group in the synthesized analogues.
authors.affiliation: Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Juncosa
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Groves
authors.forename: Guoyao
authors.initials: G
authors.lastname: Xia
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000737:chemistry* / Q000378:metabolism; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D005461:Fluorine / Q000737:chemistry*; D062105:Molecular Docking Simulation; D020888:Vigabatrin / Q000138:chemical synthesis / Q000737:chemistry*; D005680:gamma-Aminobutyric Acid / Q000737:chemistry
chemical_list: D000927:Anticonvulsants; D005461:Fluorine; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin