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

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

doi:10.1021/jm0308904

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

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

100 Citations (Scopus)

Abstract

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
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	1
Pages (from-to)	22-36
Number of pages	15
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm0308904
Publication status	Published - 2004

Keywords

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

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10.1021/jm0308904

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@article{0965b99b10ef4afc928a742699651eb7,

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

abstract = "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).",

keywords = "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",

author = "Conrad Kunick and Kathrin Lauenroth and Karen Wieking and Xu Xie and Christiane Schultz and Rick Gussio and Daniel Zaharevitz and Maryse Leost and Laurent Meijer and Alexander Weber and J{\o}rgensen, {Flemming Steen} and Thomas Lemcke",

year = "2004",

doi = "10.1021/jm0308904",

language = "English",

volume = "47",

pages = "22--36",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

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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

SN - 0022-2623

VL - 47

SP - 22

EP - 36

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -

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

Abstract

Keywords

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