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

0501629 - BTÚ 2019 RIV GB eng J - Journal Article
Bařinka, Cyril - Nováková, Zora - Hin, N. - Bím, Daniel - Ferraris, D. V. - Duvall, B. - Kabarriti, G. - Tsukamoto, R. - Buděšínský, Miloš - Motlová, Lucia - Rojas, C. - Slusher, B. S. - Rokob, T. A. - Rulíšek, Lubomír - Tsukamoto, T.
Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.
Bioorganic & Medicinal Chemistry. Roč. 27, č. 2 (2019), s. 255-264. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA MŠMT(CZ) LM2015043; GA MŠMT(CZ) EF16_013/0001776; GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR(CZ) GA17-24155S
Grant - others:Ga MŠk(CZ) LM2015070
Institutional support: RVO:86652036 ; RVO:61388963
Keywords : Glutamate carboxypeptidase II * Prostate-specific membrane antigen * Crystal structure
OECD category: Biochemistry and molecular biology; Physical chemistry (UOCHB-X)
Impact factor: 3.073, year: 2019

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.
Permanent Link: http://hdl.handle.net/11104/0293626