title: Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity.
abstract: 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.
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, BIOCEV , Prumyslova 595, 252 50 Vestec, Czech Republic.
authors.forename: Zora
authors.initials: Z
authors.lastname: Novakova
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wozniak
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , v.v.i., Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Jancarik
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, BIOCEV , Prumyslova 595, 252 50 Vestec, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Pavlicek
authors.affiliation: Department of Chemistry, McDaniel College , 2 College Hill, Westminster, Maryland 21157, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Ferraris
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, BIOCEV , Prumyslova 595, 252 50 Vestec, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Havlinova
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, BIOCEV , Prumyslova 595, 252 50 Vestec, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Ptacek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , v.v.i., Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vavra
authors.forename: Niyada
authors.initials: N
authors.lastname: Hin
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , v.v.i., Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, BIOCEV , Prumyslova 595, 252 50 Vestec, Czech Republic.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II