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

0369329 - BTÚ 2012 RIV US eng J - Journal Article
Plechanovová, Anna - Byun, Y. - Alquicer, Glenda - Škultétyová, Ĺubica - Mlčochová, Petra - Němcová, Adriana - Kim, H.-J. - Navrátil, Michal - Mease, R. - Lubkowski, J. - Pomper, M. - Konvalinka, Jan - Rulíšek, Lubomír - Bařinka, Cyril
Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity.
Journal of Medicinal Chemistry. Roč. 54, č. 21 (2011), s. 7535-7546. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) ME10031; GA MŠMT LC512
Grant - others:EMBO(DE) 1978
Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z40550506
Keywords : Glutamate carboxypeptidase II. * QM/MM calculations * X-ray crystallography * lipophilicity * inhibitors
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 5.248, year: 2011

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
Permanent Link: http://hdl.handle.net/11104/0203422