Combination of In Silico and In Vitro Screening to Identify Novel Glutamate II Inhibitors

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F23%3A00571539" target="_blank" >RIV/86652036:_____/23:00571539 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.jcim.2c01269" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jcim.2c01269</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jcim.2c01269" target="_blank" >10.1021/acs.jcim.2c01269</a>

Result language
angličtina
Original language name
Combination of In Silico and In Vitro Screening to Identify Novel Glutamate II Inhibitors
Original language description
Glutamate carboxypeptidase II (GCPII) is a metalloprotease implicated in neurological diseases and prostate oncology. While several classes of potent GCPII-specific inhibitors exist, the development of novel active scaffolds with different pharmacological profiles remains a challenge. Virtual screening followed by in vitro testing is an effective means for the discovery of novel active compounds. Structure- and ligand-based pharmacophore models were created based on a dataset of known GCPII-selective ligands. These models were used in a virtual screening of the SPECS compound library (similar to 209.000 compounds). Fifty top-scoring virtual hits were further experimentally tested for their ability to inhibit GCPII enzymatic activity in vitro. Six hits were found to have moderate to high inhibitory potency with the best virtual hit, a modified xanthene, inhibiting GCPII with an IC50 value of 353 +/- 24 nM. The identification of this novel inhibitory scaffold illustrates the applicability of pharmacophore-based modeling for the discovery of GCPII-specific inhibitors.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10406 - Analytical chemistry

Project
<a href="/en/project/GJ19-22269Y" target="_blank" >GJ19-22269Y: Development of non-canonical inhibitors of glutamate carboxypeptidase II: structure-activity relationship studies and biological activity</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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