Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones

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Conrad Kunick, Kathrin Lauenroth, Karen Wieking, Xu Xie, Christiane Schultz, Rick Gussio, Daniel Zaharevitz, Maryse Leost, Laurent Meijer, Alexander Weber, Flemming Steen Jørgensen, Thomas Lemcke

With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition data of 52 paullone entities, which were aligned by a docking routine into the ATP-binding cleft of a CDK1/cyclin B homology model. Variation of grid spacing and column filtering were used during the optimization of the models. The predictive ability of the models was shown by a leave-one-out cross-validation and the prediction of an independent set of test compounds, which were synthesized especially for this purpose. Besides paullones with the basic indolo[3,2-d][1]benzazepine core, the test set comprised novel thieno[3',2':2,3]azepino[4,5-b]indoles, pyrido[2',3':2,3]azepino[4,5-b]indoles, and a pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepine. The best statistical values for the CoMSIA were obtained for the CDK1-models (r(2)() = 0.929 and q(2)() = 0.699), which were clearly superior to the models for CDK5 (r(2)() = 0.874 and q(2)() = 0.652) and GSK-3 (r(2)() = 0.871 and q(2)() = 0.554).
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume47
Issue number1
Pages (from-to)22-36
Number of pages15
ISSN0022-2623
DOIs
Publication statusPublished - 2004

    Research areas

  • Animals, Benzazepines, CDC2 Protein Kinase, Cyclin-Dependent Kinase 3, Cyclin-Dependent Kinase 5, Cyclin-Dependent Kinases, Indoles, Models, Molecular, Protein Binding, Quantitative Structure-Activity Relationship

ID: 38394051