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

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 IC 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.

Using the Semiempirical Quantum Mechanics in Improving the Molecular Docking: A Case Study with CDK2

“…[12,[18][19][20] Many studies on various biomolecular complexes have shown that the use of the SQM methods through each of the methodologies has led to more accurate estimation of complex geometry and binding energy and consequently has increased the docking accuracy. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] In this study, a post-docking optimization with the different popular corrected SQM Hamiltonians has been performed for the docking results of a series of human cyclin-dependent kinase 2 (CDK2). The CDK2 is a serine/ threonine-protein kinase that is activated by binding to a regulatory cyclin protein for the cell cycle progression and transcription.…”

“…[24][25][26] Furthermore, from the computational point of view, the adequate availability of complex X-ray crystal structures of CDK2 with various ligands (within the ATP binding site) and their affinity data makes CDK2 a very interesting target for docking studies. [17,[20][21][22][23][27][28][29][30] 2 Methods…”

Inactivating Activities and Mechanism of Imidazo[1,2-c]pyrimidin-5(6H)-one Nucleoside Derivatives Incorporating a Sulfonamide Scaffold

“…And B17, B25, and B29 were randomly deprotected to obtain B30−B32. The structures of B1−B32 were further identified by 1 H NMR, 13 C NMR, 19 F NMR, and HRMS. In addition, B7 was dissolved in a mixed solution of ethyl acetate and ethanol, and a single crystal of B7 was obtained by slow crystallization at rt.…”

“…■ ABBREVIATIONS 1 H NMR, 1 H nuclear magnetic resonance; 13 C NMR, 13 C nuclear magnetic resonance; 19 F NMR, 19 F nuclear magnetic resonance; HRMS, high-resolution mass spectrometry; PMMoV, pepper mild mottle virus; CP, coat protein; EC 50 , half-maximal effective concentration; DPI, days post-inoculation; 3D-QSAR, three-dimensional quantitative structure− activity relationship; CoMFA, comparative molecular field analysis; CoMSIA, comparative molecular similarity index analysis; ONC, optimal number of components; SEE, standard error of estimate; Q LOO 2 , cross-validation coefficient; F, Fisher statistic; R 2 , non-cross-validated correlation coefficient; CCC, consistency correlation coefficient; LOO, leave-one-out method; Q 2 , external prediction correlation coefficient; TEM, transmission electron microscopy; MST, microscale thermophoresis; SDS−PAGE, sodium dodecyl sulfate−polyacrylamide gel electrophoresis; K d , dissociation constant; GFP, green fluorescent protein; RT-qPCR, reverse transcription-quantitative polymerase chain reaction…”

3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

“…The protein structures were prepared using the protein preparation wizard in Maestro with default setting. Grids were generated using Glide, following the default procedure used according to our previous work protocol. ,, The conformational ensembles were docked flexibly using Glide with default setting in both standard precision and extra precision modes. Only poses with low energy conformations and good hydrogen bond geometries were considered.…”