Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones
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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 language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 47 |
Issue number | 1 |
Pages (from-to) | 22-36 |
Number of pages | 15 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2004 |
- 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
Research areas
ID: 38394051