Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity

Anna Plechanovová, Youngjoo Byun, Glenda Alquicer, L'Ubica Škultétyová, Petra Mlčochová, Adriana Němcová, Hyung Joon Kim, Michal Navrátil, Ronnie Mease, Jacek Lubkowski, Martin Pomper, Jan Konvalinka, Lubomír Rulíšek, Cyril Bařinka

Research output: Contribution to journalArticle

Abstract

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here 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. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1′ specificity pocket. 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.

Original languageEnglish (US)
Pages (from-to)7535-7546
Number of pages12
JournalJournal of medicinal chemistry
Volume54
Issue number21
DOIs
StatePublished - Nov 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Plechanovová, A., Byun, Y., Alquicer, G., Škultétyová, LU., Mlčochová, P., Němcová, A., Kim, H. J., Navrátil, M., Mease, R., Lubkowski, J., Pomper, M., Konvalinka, J., Rulíšek, L., & Bařinka, C. (2011). Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity. Journal of medicinal chemistry, 54(21), 7535-7546. https://doi.org/10.1021/jm200807m