European Biophysics Journal

, Volume 39, Issue 9, pp 1365–1372

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

  • Olivier Sperandio
  • Liliane Mouawad
  • Eulalie Pinto
  • Bruno O. Villoutreix
  • David Perahia
  • Maria A. Miteva
Biophysics Letter

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.

Keywords

Receptor flexibility Docking Virtual screening Normal modes Cdk2 

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Copyright information

© European Biophysical Societies' Association 2010

Authors and Affiliations

  • Olivier Sperandio
    • 1
  • Liliane Mouawad
    • 2
    • 3
  • Eulalie Pinto
    • 1
  • Bruno O. Villoutreix
    • 1
  • David Perahia
    • 4
  • Maria A. Miteva
    • 1
  1. 1.MTI, Inserm UMR-S 973University Paris DiderotParisFrance
  2. 2.Institut Curie, Centre de RechercheOrsay CedexFrance
  3. 3.Inserm U759Centre Universitaire d’OrsayOrsay CedexFrance
  4. 4.Institut de Biochimie et Biophysique Moléculaire et CellulaireUniversité Paris-SudOrsayFrance

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