Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones
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Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones. / Kunick, Conrad; Lauenroth, Kathrin; Wieking, Karen; Xie, Xu; Schultz, Christiane; Gussio, Rick; Zaharevitz, Daniel; Leost, Maryse; Meijer, Laurent; Weber, Alexander; Jørgensen, Flemming Steen; Lemcke, Thomas.
In: Journal of Medicinal Chemistry, Vol. 47, No. 1, 2004, p. 22-36.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones
AU - Kunick, Conrad
AU - Lauenroth, Kathrin
AU - Wieking, Karen
AU - Xie, Xu
AU - Schultz, Christiane
AU - Gussio, Rick
AU - Zaharevitz, Daniel
AU - Leost, Maryse
AU - Meijer, Laurent
AU - Weber, Alexander
AU - Jørgensen, Flemming Steen
AU - Lemcke, Thomas
PY - 2004
Y1 - 2004
N2 - 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).
AB - 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).
KW - Animals
KW - Benzazepines
KW - CDC2 Protein Kinase
KW - Cyclin-Dependent Kinase 3
KW - Cyclin-Dependent Kinase 5
KW - Cyclin-Dependent Kinases
KW - Indoles
KW - Models, Molecular
KW - Protein Binding
KW - Quantitative Structure-Activity Relationship
U2 - 10.1021/jm0308904
DO - 10.1021/jm0308904
M3 - Journal article
C2 - 14695817
VL - 47
SP - 22
EP - 36
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
ID: 38394051