ArticleJournal of the American Chemical Society2015
Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator.Journal of the American Chemical Society · 2026Article
- Design, synthesis and acaricidal activity of tetrahydrothiophene derivatives againstRSC advances · 2025Article
- Systematic, computational discovery of multicomponent and one-pot reactions.Nature communications · 2024Article
- Synthesis of (2The Journal of organic chemistry · 2024Article
- FromiScience · 2024Article
- Identification of novel C-15 fluoro isosteviol derivatives for GABA-AT inhibition by in silico investigations.Journal of molecular modeling · 2023Article
- Structural and Kinetic Analyses Reveal the Dual Inhibition Modes of Ornithine Aminotransferase by (1ACS chemical biology · 2021Article
- (S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR.Protein science : a publication of the Protein Society · 2020Article
- QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT.Molecules (Basel, Switzerland) · 2018Article
- Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme fromMolecules (Basel, Switzerland) · 2018Article
- Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions.Chemical reviews · 2018Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S···O═C interaction with Glu-270, thereby inactivating the enzyme.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.