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.
Original language | English (US) |
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Pages (from-to) | 903-911 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 21 |
Issue number | 4 |
DOIs | |
State | Published - Feb 15 2013 |
Keywords
- 4-Amino-5- fluoropentanoic acid
- Enzyme inhibition
- Molecular dynamics
- Vigabatrin
- γ-Aminobutyric acid aminotransferase
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry