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

Jiri Pavlicek, Jakub Ptacek, Jiri Cerny, Youngjoo Byun, Lubica Skultetyova, Martin G. Pomper, Jacek Lubkowski, Cyril Barinka

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2340-2345
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number10
DOIs
StatePublished - May 15 2014

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Structural characterization of P1′-diversified urea-based inhibitors of glutamate carboxypeptidase II'. Together they form a unique fingerprint.

Cite this