Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity

0469171 - BTÚ 2017 RIV US eng J - Journal Article
Nováková, Zora - Wozniak, K. - Jančařík, Andrej - Rais, R. - Wu, Y. - Pavlíček, Jiří - Ferraris, D. - Havlínová, Barbora - Ptáček, Jakub - Vávra, Jan - Hin, N. - Rojas, C. - Majer, Pavel - Slusher, B. S. - Tsukamoto, T. - Bařinka, Cyril
Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity.
Journal of Medicinal Chemistry. Roč. 59, č. 10 (2016), s. 4539-4550. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR GAP301/12/1513
Institutional support: RVO:86652036 ; RVO:61388963
Keywords : LINKED ACIDIC DIPEPTIDASE * N-ACETYLASPARTYLGLUTAMATE NAAG * THIOL-BASED INHIBITORS
Subject RIV: FR - Pharmacology ; Medidal Chemistry; CC - Organic Chemistry (UOCHB-X)
Impact factor: 6.259, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0267014