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Molecular Mechanism of Interaction of Paullones with Kinases— Structure/Activity Relationship Studies

Kinetic studies revealed that paullones inhibit kinases by competition with ATP for binding to the catalytic site (Zaharevitz et al. 1999). Since the initial

Fig. 5 Hydrogen bonds between CDK1/cyclin B and a 9-sulphamoyl-substituted paullone docked to the ATP-binding pocket. This illustration was created using SYBYL (Version 6.7, Tripos Inc. St. Louis, Missouri 63144, USA), employing the CDK1/cyclin B homology model developed by R. Gussio (Gussio et al. 2000). The manual docking and the subsequent minimisation process, performed using the MAB force field implemented in the program MOLOC (Gerber 1998), were carried out by T. Lemcke, University of Hamburg. To improve clarity of the illustration, the side chains of the amino acids glutamic acid-81 through methionine-85 are not depicted. The dotted lines represent the hydrogen bonds formed between the paullone molecule and the amino acids leucine-83 and aspartic acid-86. (This figure comes from the dissertation thesis of T. Pies)

Fig. 5 Hydrogen bonds between CDK1/cyclin B and a 9-sulphamoyl-substituted paullone docked to the ATP-binding pocket. This illustration was created using SYBYL (Version 6.7, Tripos Inc. St. Louis, Missouri 63144, USA), employing the CDK1/cyclin B homology model developed by R. Gussio (Gussio et al. 2000). The manual docking and the subsequent minimisation process, performed using the MAB force field implemented in the program MOLOC (Gerber 1998), were carried out by T. Lemcke, University of Hamburg. To improve clarity of the illustration, the side chains of the amino acids glutamic acid-81 through methionine-85 are not depicted. The dotted lines represent the hydrogen bonds formed between the paullone molecule and the amino acids leucine-83 and aspartic acid-86. (This figure comes from the dissertation thesis of T. Pies)

discovery of paullones, more than 60 analogues have been synthesised, leading to compounds active in the nanomolar range (Schultz et al. 1999; Kunick et al. 2000; Leost et al. 2000). In addition, this SAR study has provided some information on the mechanism of interaction of paullones with their kinase targets. Recently, 3D-QSAR CoMSIA models were developed for the inhibition of CDKl/cyclin B, CDK5/p25 and GSK-3b by the paullones family (Kunick et al. 2004). The models were based on the kinase inhibition data of 52 paullones, docked into the ATP-binding site of a CDK1 homology model (Gussio et al. 2000) (Fig. 5). Recently, alsterpaullone has also been crystallised with GSK-3b (Bertrand et al. 2003). The co-crystal structure confirms that alsterpaullone is binding in the ATP-binding pocket. The interactions include hydrogen bonds with aspartic acid 133 and valine 135, as observed for other inhibitors recently crystallised with GSK-3b, 6-bromo-indirubin-3'-oxime (Meijer et al. 2003), indirubin-3'-oxime, I-5 and stau-rosporine (Bertrand et al. 2003) and the thiazole AR-A014418 (Bhat et al. 2003) (see review in Fischer 2003).

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