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Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

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Abstract

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.

Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.

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Acknowledgments

The authors thank Professor Arthur J. Olson for his kindness in offering us the AutoDock 3.0.3 program. We also thank Dr. Holger Gohlke for his help with free energy calculations. Jiang YJ acknowledges Prof. Jiang Hualiang.

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Authors and Affiliations

  1. Key Laboratory for Molecular Design and Nutrition Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo, 315104, P.R. China

    Yongjun Jiang & Jianwei Zou

  2. Center for Drug Discovery and Design, Shanghai Institute of Materia Medica, Shanghai, 200031, P.R. China

    Chunshan Gui

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  1. Yongjun Jiang
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  2. Jianwei Zou
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  3. Chunshan Gui
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Correspondence to Yongjun Jiang.

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Jiang, Y., Zou, J. & Gui, C. Study of a ligand complexed with Cdk2/Cdk4 by computer simulation. J Mol Model 11, 509–515 (2005). https://doi.org/10.1007/s00894-005-0263-8

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