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Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

SYSNO ASEP	0369329
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity
Author(s)	Plechanovová, Anna (UOCHB-X) Byun, Y. (US) Alquicer, Glenda (BTO-N) Škultétyová, Ĺubica (BTO-N)_RID Mlčochová, Petra (UOCHB-X) Němcová, Adriana (UOCHB-X) Kim, H.-J. (US) Navrátil, Michal (UOCHB-X)_RID Mease, R. (US) Lubkowski, J. (US) Pomper, M. (US) Konvalinka, Jan (UOCHB-X)_{RID, ORCID} Rulíšek, Lubomír (UOCHB-X)_{RID, ORCID} Bařinka, Cyril (BTO-N)_{RID, ORCID}
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 54, č. 21 (2011), s. 7535-7546
Number of pages	12 s.
Language	eng - English
Country	US - United States
Keywords	Glutamate carboxypeptidase II. ; QM/MM calculations ; X-ray crystallography ; lipophilicity ; inhibitors
Subject RIV	EB - Genetics ; Molecular Biology
R&D Projects	ME10031 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	LC512 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
CEZ	AV0Z50520701 - BTO-N (2007-2013)
	AV0Z40550506 - UOCHB-X (2005-2011)
UT WOS	000296408100010
DOI	10.1021/jm200807m
Annotation	We report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII
Workplace	Institute of Biotechnology
Contact	Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700
Year of Publishing	2012

Number of the records: 1