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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Pavlicek, Jiri¹  Ptacek, Jakub¹  Cerny, Jiri¹  Byun, Youngjoo^2,3  Skultetyova, Lubica¹  Pomper, Martin G.²  Lubkowski, Jacek⁴  Barinka, Cyril¹ 

[1] Acad Sci Czech Republ, Inst Biotechnol, Struct Biol Lab, Vvi, Prague 14220 4, Czech Republic

[2] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21231 USA

[3] Korea Univ, Coll Pharm, Sejong 339700, South Korea

[4] Ctr Canc Res, Frederick Natl Lab Canc Res, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA

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

DOI  :  10.1016/j.bmcl.2014.03.066

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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