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

doi:10.1016/j.bmcl.2014.03.066

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 language	English (US)
Pages (from-to)	2340-2345
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2014.03.066
State	Published - 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

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10.1016/j.bmcl.2014.03.066

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@article{407dea6ad6374cf6a2a0efc75d4aa02a,

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.",

keywords = "GCPII, Metallopeptidase, PSMA, Prostate-specific membrane antigen, Structure-based drug design, Urea-based inhibitor, X-ray crystallography",

author = "Jiri Pavlicek and Jakub Ptacek and Jiri Cerny and Youngjoo Byun and Lubica Skultetyova and Pomper, {Martin G.} and Jacek Lubkowski and Cyril Barinka",

note = "Funding Information: The authors acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38 . C.B. acknowledges the support from the EMBO (Installation Grant 1978) and IRG (project number 249220). This publication is supported by the project {\textquoteleft}BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University{\textquoteright} (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund, by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (to J.L.), by NIH R01 CA134675 (to M.G.P.), and by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MEST) (No. 2012R1A1A1010000; to Y.B.). ",

year = "2014",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2014.03.066",

language = "English (US)",

volume = "24",

pages = "2340--2345",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Structural characterization of P1′-diversified urea-based inhibitors of glutamate carboxypeptidase II

AU - Pavlicek, Jiri

AU - Ptacek, Jakub

AU - Cerny, Jiri

AU - Byun, Youngjoo

AU - Skultetyova, Lubica

AU - Pomper, Martin G.

AU - Lubkowski, Jacek

AU - Barinka, Cyril

N1 - Funding Information: The authors acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38 . C.B. acknowledges the support from the EMBO (Installation Grant 1978) and IRG (project number 249220). This publication is supported by the project ‘BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University’ (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund, by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (to J.L.), by NIH R01 CA134675 (to M.G.P.), and by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MEST) (No. 2012R1A1A1010000; to Y.B.).

PY - 2014/5/15

Y1 - 2014/5/15

N2 - 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.

AB - 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.

KW - GCPII

KW - Metallopeptidase

KW - PSMA

KW - Prostate-specific membrane antigen

KW - Structure-based drug design

KW - Urea-based inhibitor

KW - X-ray crystallography

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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