Imidazo[1,2-c]pyrimidin-5(6H)-one as a novel core of cyclin-dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring

0492387 - ÚOCHB 2019 RIV GB eng J - Journal Article
Ajani, Haresh - Jansa, J. - Köprülüoglu, Cemal - Hobza, Pavel - Kryštof, Vladimír - Lyčka, A. - Lepšík, Martin
Imidazo[1,2-c]pyrimidin-5(6H)-one as a novel core of cyclin-dependent kinase 2 inhibitors: Synthesis, activity measurement, docking, and quantum mechanical scoring.
Journal of Molecular Recognition. Roč. 31, č. 9 (2018), č. článku e2720. ISSN 0952-3499. E-ISSN 1099-1352
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963 ; RVO:61389030
Keywords : binding mode * physics-based scoring * protein-ligand binding
OECD category: Biophysics
Impact factor: 1.919, year: 2018

We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge-region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8-substituents. Semiempirical quantum mechanics-based scoring identified probable favourable binding modes, which will serve for future structure-based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases.
Permanent Link: http://hdl.handle.net/11104/0285946