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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F19%3A00501629" target="_blank" >RIV/86652036:_____/19:00501629 - isvavai.cz</a>

Alternative codes found

RIV/61388963:_____/19:00501629

Result on the web

<a href="http://dx.doi.org/10.1016/j.bmc.2018.11.022" target="_blank" >http://dx.doi.org/10.1016/j.bmc.2018.11.022</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2018.11.022" target="_blank" >10.1016/j.bmc.2018.11.022</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Bioorganic & Medicinal Chemistry

ISSN

0968-0896

e-ISSN

—

Volume of the periodical

27

Issue of the periodical within the volume

2

Country of publishing house

GB - UNITED KINGDOM

Number of pages

10

Pages from-to

255-264

UT code for WoS article

000456082000001

EID of the result in the Scopus database

2-s2.0-85058053256