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.
J Mol Recognit
; 31(9): e2720, 2018 09.
Article
en En
| MEDLINE
| ID: mdl-29687635
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Inhibidores de Proteínas Quinasas
/
Quinasa 2 Dependiente de la Ciclina
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Mol Recognit
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2018
Tipo del documento:
Article
País de afiliación:
República Checa