Journal article
Probing the steric requirements of the gamma-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin
Bioorganic & medicinal chemistry, Vol.21(4), pp.903-911
02/15/2013
DOI: 10.1016/j.bmc.2012.12.009
PMCID: PMC3563932
PMID: 23306054
Abstract
We have synthesized three analogues of 4-amino-5-fluorohexanoic acids as potential inactivators of gamma-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 (R)). 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. (C) 2012 Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Probing the steric requirements of the gamma-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin
- Creators
- Jose I. Juncosa - Northwestern UniversityAndrew P. Groves - Northwestern UniversityGuoyao Xia - Northwestern UniversityRichard B. Silverman - Northwestern University
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry, Vol.21(4), pp.903-911
- DOI
- 10.1016/j.bmc.2012.12.009
- PMID
- 23306054
- PMCID
- PMC3563932
- NLM abbreviation
- Bioorg Med Chem
- ISSN
- 0968-0896
- eISSN
- 1464-3391
- Publisher
- Elsevier
- Number of pages
- 9
- Grant note
- R01DA030604 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission R01GM066132 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) GM066132; DA030604 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 02/15/2013
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984354524402771
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