Počet záznamů: 1

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

  1. 1.
    0369329 - BTO-N 2012 RIV US eng J - Článek v odborném periodiku
    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
    Grant CEP: GA MŠk(CZ) ME10031; GA MŠk LC512
    Grant ostatní: EMBO(DE) 1978
    Výzkumný záměr: CEZ:AV0Z50520701; CEZ:AV0Z40550506
    Klíčová slova: Glutamate carboxypeptidase II. * QM/MM calculations * X-ray crystallography * lipophilicity * inhibitors
    Kód oboru RIV: EB - Genetika a molekulární biologie
    Impakt faktor: 5.248, rok: 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
    Trvalý link: http://hdl.handle.net/11104/0203422
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