Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors

Cyril Barinka, Zora Novakova, Niyada Hin, Daniel Bím, Dana V. Ferraris, Bridget Duvall, Gabriel Kabarriti, Reiji Tsukamoto, Milos Budesinsky, Lucia Motlova, Camilo Rojas, Barbara S. Slusher, Tibor András Rokob, Lubomír Rulíšek, Takashi Tsukamoto

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-L-glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII's preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt a nearly identical binding mode while (R,S)-carbamate analog 8 containing a D-leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number2
DOIs
Publication statusPublished - Jan 15 2019

Keywords

  • Crystal structure
  • Glutamate carboxypeptidase II
  • Metallopeptidase
  • Prostate-specific membrane antigen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Barinka, C., Novakova, Z., Hin, N., Bím, D., Ferraris, D. V., Duvall, B., Kabarriti, G., Tsukamoto, R., Budesinsky, M., Motlova, L., Rojas, C., Slusher, B. S., Rokob, T. A., Rulíšek, L., & Tsukamoto, T. (2019). Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors. Bioorganic and Medicinal Chemistry, 27(2), 255-264. https://doi.org/10.1016/j.bmc.2018.11.022