Abstract
Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q 2 = 0.695, r 2 = 0.947) and CoMSIA model (q 2 = 0.641, r 2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r 2 pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.
Highlights
Cyclin-dependent kinases (CDKs), a family of serine/threonine protein kinases, play a central role in the growth, development, proliferation and death of eukaryotic cells [1,2]
There are more than 13 CDKs of which 12 different cyclin families have been identified up to now, and different CDK/cyclin combinations are active during each phase of the cell cycle [3,4,5]
This kind of function exerted by D/CDK4 and E/ CDK2 complexes is positively regulated by the mitogenic signaling pathways and negatively regulated by the cyclin-dependent kinase inhibitors (CKIs) [7,8,9,10,11,12,13]
Summary
Cyclin-dependent kinases (CDKs), a family of serine/threonine protein kinases, play a central role in the growth, development, proliferation and death of eukaryotic cells [1,2]. There are more than 13 CDKs of which 12 different cyclin families have been identified up to now, and different CDK/cyclin combinations are active during each phase of the cell cycle [3,4,5]. Phosphorylation of the Rb activated the E2F transcription factors and resulted in the transcription of genes required for DNA synthesis. This kind of function exerted by D/CDK4 and E/ CDK2 complexes is positively regulated by the mitogenic signaling pathways and negatively regulated by the cyclin-dependent kinase inhibitors (CKIs) [7,8,9,10,11,12,13]. A series of novel isoquinoline-1, 3-(2H, 4H)diones have been found to possess excellent selective inhibitory activity against the CDK4 [7,8]
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