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).
authors.affiliation: Institut für Pharmazie, Abteilung für Pharmazeutische Chemie, Universität Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.forename: Kathrin
authors.initials: K
authors.lastname: Lauenroth
authors.forename: Karen
authors.initials: K
authors.lastname: Wieking
authors.forename: Xu
authors.initials: X
authors.lastname: Xie
authors.forename: Christiane
authors.initials: C
authors.lastname: Schultz
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Daniel
authors.initials: D
authors.lastname: Zaharevitz
authors.forename: Maryse
authors.initials: M
authors.lastname: Leost
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Alexander
authors.initials: A
authors.lastname: Weber
authors.forename: Flemming S
authors.initials: FS
authors.lastname: Jørgensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056849:Cyclin-Dependent Kinase 3; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D007211:Indoles; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; C098776:CDK3 protein, human; D056849:Cyclin-Dependent Kinase 3; D018844:Cyclin-Dependent Kinases