Optimization of norbornyl‐based carbocyclic nucleoside analogs as cyclin‐dependent kinase 2 inhibitors. Issue 8 (25th March 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of molecular recognition. Volume 33:Issue 8(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-25
• Subjects: ATP‐competitive type I inhibitors -- cyclin‐dependent kinase 2 -- protein‐ligand binding -- quantum mechanical scoring; Molecular recognition -- Periodicals; Models, Molecular -- Periodicals; Molecular Conformation -- Periodicals; Molecular Sequence Data -- Periodicals; Molecular Structure -- Periodicals; Carrier Proteins -- Periodicals; 572.8
• DOI: 10.1002/jmr.2842
• Languages: English
• ISSNs: 0952-3499

Abstract

Abstract: 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. Abstract :