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PDBsum entry 6fe5
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References listed in PDB file
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Key reference
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Title
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Structural and computational basis for potent inhibition of glutamate carboxypeptidase ii by carbamate-Based inhibitors.
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Authors
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C.Barinka,
Z.Novakova,
N.Hin,
D.Bím,
D.V.Ferraris,
B.Duvall,
G.Kabarriti,
R.Tsukamoto,
M.Budesinsky,
L.Motlova,
C.Rojas,
B.S.Slusher,
T.A.Rokob,
L.Rulíšek,
T.Tsukamoto.
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Ref.
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Bioorg Med Chem, 2019,
27,
255-264.
[DOI no: ]
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PubMed id
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Abstract
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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.
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