An in silico approach for the discovery of CDK5/p25 interaction inhibitors

Authors

  • Bing Zhang,

    1. Thermal Physics Center, School of Renewable Energy, North China Electric Power University, Beijing, China
    2. Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
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  • Caroline Corbel,

    1. CNRS USR3151, Protein Phosphorylation & Disease Laboratory, Protein-Protein Interaction Inhibition P2I2 Group, Station Biologique, Roscoff, Bretagne, France
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  • Françoise Guéritte,

    1. CNRS UPR 2301, Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Gif-sur-Yvette cedex, France
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  • Cyril Couturier,

    1. INSERM U761 Biostructures and Drug Discovery, Université Lille Nord de France; Institut Pasteur de Lille, Pôle de Recherche Interdisciplinaire pour le Medicament, Lille, France
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  • Stéphane Bach,

    1. CNRS USR3151, Protein Phosphorylation & Disease Laboratory, Protein-Protein Interaction Inhibition P2I2 Group, Station Biologique, Roscoff, Bretagne, France
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  • Dr. Vincent B. C. Tan

    Corresponding author
    1. Thermal Physics Center, School of Renewable Energy, North China Electric Power University, Beijing, China
    • Department of Mechanical Engineering, National University of Singapore, 9 Engineering Drive 1, 117576 Kent Ridge, Singapore
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Abstract

The lack of selectivity of all existing ATP competitive inhibitors for a single cyclin-dependent kinase (CDK) has led us to redirect the structure-based molecule design from targeting the classic ATP-binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein-protein interactions. A combined strategy of alanine-scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio-assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs.

Accompanying article Corbel et al.

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