Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity
Language English Country United States Media print-electronic
Document type Journal Article
- MeSH
- Antigens, Surface metabolism MeSH
- Glutamate Carboxypeptidase II antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Hydroxamic Acids chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antigens, Surface MeSH
- FOLH1 protein, human MeSH Browser
- Glutamate Carboxypeptidase II MeSH
- Enzyme Inhibitors MeSH
- Hydroxamic Acids MeSH
Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket. This unique binding mode provides a mechanistic explanation for the structure-activity relationship data, most notably the lack of enantiospecificity and the tolerance for bulky/hydrophobic functions as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics profile of one of the inhibitors will be presented along with analgesic efficacy data from the rat chronic constrictive injury model of neuropathic pain.
References provided by Crossref.org
Uncovering the essential roles of glutamate carboxypeptidase 2 orthologs in Caenorhabditis elegans
