Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00523373" target="_blank" >RIV/61388963:_____/20:00523373 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/61389030:_____/20:00523373 RIV/61989592:15310/20:73603992
Výsledek na webu
<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/jmr.2842" target="_blank" >https://onlinelibrary.wiley.com/doi/abs/10.1002/jmr.2842</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/jmr.2842" target="_blank" >10.1002/jmr.2842</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors
Popis výsledku v původním jazyce
We report on the discovery of norbornyl moiety as a novel structural motif for cyclin‐dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.
Název v anglickém jazyce
Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors
Popis výsledku anglicky
We report on the discovery of norbornyl moiety as a novel structural motif for cyclin‐dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
10403 - Physical chemistry
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2020
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Journal of Molecular Recognition
ISSN
0952-3499
e-ISSN
—
Svazek periodika
33
Číslo periodika v rámci svazku
8
Stát vydavatele periodika
GB - Spojené království Velké Británie a Severního Irska
Počet stran výsledku
16
Strana od-do
e2842
Kód UT WoS článku
000549952000002
EID výsledku v databázi Scopus
2-s2.0-85082200932