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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
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SYSNO ASEP 0492387 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 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 Author(s) Ajani, Haresh (UOCHB-X) ORCID, RID
Jansa, J. (CZ)
Köprülüoglu, Cemal (UOCHB-X) ORCID, RID
Hobza, Pavel (UOCHB-X) RID, ORCID
Kryštof, Vladimír (UEB-Q) RID, ORCID
Lyčka, A. (CZ)
Lepšík, Martin (UOCHB-X) RID, ORCIDArticle number e2720 Source Title Journal of Molecular Recognition. - : Wiley - ISSN 0952-3499
Roč. 31, č. 9 (2018)Number of pages 11 s. Language eng - English Country GB - United Kingdom Keywords binding mode ; physics-based scoring ; protein-ligand binding Subject RIV BO - Biophysics OECD category Biophysics R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UOCHB-X - RVO:61388963 ; UEB-Q - RVO:61389030 UT WOS 000441248700002 EID SCOPUS 85045844397 DOI 10.1002/jmr.2720 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2019
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