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Bioorg Med Chem Lett. 2014 May 15;24(10):2340-5. doi: 10.1016/j.bmcl.2014.03.066. Epub 2014 Mar 28.

Structural characterization of P1'-diversified urea-based inhibitors of glutamate carboxypeptidase II.

Author information

1
Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
2
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.
3
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
4
Center for Cancer Research, Frederick National Laboratory for Cancer Research, Macromolecular Crystallography Laboratory, Frederick, MD 21702, USA.
5
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.

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.

KEYWORDS:

GCPII; Metallopeptidase; PSMA; Prostate-specific membrane antigen; Structure-based drug design; Urea-based inhibitor; X-ray crystallography

PMID:
24731280
PMCID:
PMC4077459
DOI:
10.1016/j.bmcl.2014.03.066
[Indexed for MEDLINE]
Free PMC Article
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