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How to choose relevant multiple receptor conformations for virtual screening: a test case of Cdk2 and normal mode analysis

  • Biophysics Letter
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Abstract

Better treatment of protein flexibility is essential in structure-based drug design projects such as virtual screening and protein-ligand docking. Diversity in ligand-binding mechanisms and receptor conformational changes makes it difficult to treat dynamic features of the receptor during the docking simulation. Thus, the use of pregenerated multiple receptor conformations is applied today in virtual screening studies. However, generation of a small relevant set of receptor conformations remains challenging. To address this problem, we propose a new protocol for the generation of multiple receptor conformations via normal mode analysis and for the selection of several receptor conformations suitable for docking/virtual screening. We validated this protocol on cyclin-dependent kinase 2, which possesses a binding site located at the interface between two subdomains and is known to undergo significant conformational changes in the active site region upon ligand binding. We believe that the suggested rules for the choice of suitable receptor conformations can be applied to other targets when dealing with in silico screening on flexible receptors.

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Acknowledgments

Support from the French National Research Institutes Inserm, CNRS, and the Institute Curie is greatly appreciated, as is that of the University Paris Diderot and University Paris-sud 11. We thank Dr. Jain for providing the Surflex program.

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Authors and Affiliations

  1. MTI, Inserm UMR-S 973, University Paris Diderot, 35 Rue Hélène Brion, 75013, Paris, France

    Olivier Sperandio, Eulalie Pinto, Bruno O. Villoutreix & Maria A. Miteva

  2. Institut Curie, Centre de Recherche, 91405, Orsay Cedex, France

    Liliane Mouawad

  3. Inserm U759, Centre Universitaire d’Orsay, Bât 112, 91405, Orsay Cedex, France

    Liliane Mouawad

  4. Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Université Paris-Sud, Bât 430, 91405, Orsay, France

    David Perahia

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  1. Olivier Sperandio
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  2. Liliane Mouawad
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  3. Eulalie Pinto
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  4. Bruno O. Villoutreix
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  5. David Perahia
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  6. Maria A. Miteva
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Correspondence to Maria A. Miteva.

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Sperandio, O., Mouawad, L., Pinto, E. et al. How to choose relevant multiple receptor conformations for virtual screening: a test case of Cdk2 and normal mode analysis. Eur Biophys J 39, 1365–1372 (2010). https://doi.org/10.1007/s00249-010-0592-0

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  • DOI: https://doi.org/10.1007/s00249-010-0592-0

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