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Optimization of norbornyl‐based carbocyclic nucleoside analogs as cyclin‐dependent kinase 2 inhibitors
Author(s) -
Köprülüoğlu Cemal,
Dejmek Milan,
Šála Michal,
Ajani Haresh,
Hřebabecký Hubert,
Fanfrlík Jindřich,
Jorda Radek,
Dračínský Martin,
Procházková Eliška,
Šácha Pavel,
Kryštof Vladimír,
Hobza Pavel,
Lepšík Martin,
Nencka Radim
Publication year - 2020
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.2842
Subject(s) - moiety , chemistry , nucleoside , docking (animal) , stereochemistry , combinatorial chemistry , 2 norbornyl cation , kinase , drug discovery , substituent , computational biology , biochemistry , biology , medicine , nursing
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 IC 50 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.