How to choose relevant multiple receptor conformations for virtual screening: a test case of Cdk2 and normal mode analysis |
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Authors: | Olivier Sperandio Liliane Mouawad Eulalie Pinto Bruno O Villoutreix David Perahia Maria A Miteva |
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Institution: | 1. MTI, Inserm UMR-S 973, University Paris Diderot, 35 Rue Hélène Brion, 75013, Paris, France 2. Institut Curie, Centre de Recherche, 91405, Orsay Cedex, France 3. Inserm U759, Centre Universitaire d’Orsay, Bat 112, 91405, Orsay Cedex, France 4. Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Université Paris-Sud, Bat 430, 91405, Orsay, France
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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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