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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, Surface / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / chemistry
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Protein Conformation
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemistry
  • Urea / pharmacology

Substances

  • Antigens, Surface
  • Enzyme Inhibitors
  • Urea
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II