Insight into the interactions between novel isoquinolin-1,3-dione derivatives and cyclin-dependent kinase 4 combining QSAR and molecular docking.
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 (q2 = 0.695, r2 = 0.947) and CoMSIA model (q2 = 0.641, r2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r2pred 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.
Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, P. R. China.
Junxia
J
Zheng
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
Hao
H
Kong
Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
James M
JM
Wilson
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
Jialiang
J
Guo
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
Yiqun
Y
Chang
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
Mengjia
M
Yang
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
Gaokeng
G
Xiao
Department of Medicinal Chemistry, College of Pharmacy, Jinan University, Guangzhou, P. R. China; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America; College of Pharmacy, University of South Florida, Tampa, Florida, United States of America.
Pinghua
P
Sun
D000255:Adenosine Triphosphate / Q000737:chemistry; D000465:Algorithms; D019295:Computational Biology; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry*; D008024:Ligands; D015233:Models, Statistical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013329:Structure-Activity Relationship
C472069:1,3(2H,4H)-isoquinolinedione; D007546:Isoquinolines; D008024:Ligands; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4