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) |
|---|---|
| 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 |
Funding
The authors are grateful to the National Institutes of Health (GM066132 and DA030604) for financial support of this research and to Amit Walia for assistance in determining the purity of the final compounds.
Keywords
- 4-Amino-5- fluoropentanoic acid
- Enzyme inhibition
- Molecular dynamics
- Vigabatrin
- γ-Aminobutyric acid aminotransferase
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Molecular Biology
- Biochemistry
- Clinical Biochemistry
- Pharmaceutical Science
- Organic Chemistry