title: Structural characterization of P1'-diversified urea-based inhibitors of glutamate carboxypeptidase II.
abstract: Urea-based inhibitors of human glutamate carboxypeptidase II (GCPII) have advanced into clinical trials for imaging metastatic prostate cancer. In parallel efforts, agents with increased lipophilicity have been designed and evaluated for targeting GCPII residing within the neuraxis. Here we report the structural and computational characterization of six complexes between GCPII and P1'-diversified urea-based inhibitors that have the C-terminal glutamate replaced by more hydrophobic moieties. The X-ray structures are complemented by quantum mechanics calculations that provide a quantitative insight into the GCPII/inhibitor interactions. These data can be used for the rational design of novel glutamate-free GCPII inhibitors with tailored physicochemical properties.
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Pavlicek
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Ptacek
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Cerny
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA; College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 339-700, South Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Skultetyova
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Center for Cancer Research, Frederick National Laboratory for Cancer Research, Macromolecular Crystallography Laboratory, Frederick, MD 21702, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic. Electronic address: cyril.barinka@img.cas.cz.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
mesh_terms: D000954:Antigens, Surface / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: GCPII; Metallopeptidase; PSMA; Prostate-specific membrane antigen; Structure-based drug design; Urea-based inhibitor; X-ray crystallography
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