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WIREs Comput Mol Sci
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Receptor flexibility in small‐molecule docking calculations

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Abstract Protein structural flexibility plays a critical role in receptor–ligand binding processes and should be considered in computational drug design. However, the treatment of protein conformational changes is still a major challenge because it is associated with a large increase in the conformational space that needs to be sampled and requires highly accurate scoring functions that incorporate the receptor reorganization energy. A number of different approaches have been proposed recently to address this problem. Most of them have been shown to be successful in reproducing the correct docking pose of known ligands, but their benefit regarding enrichment, affinity prediction, and screening of large molecular libraries is less clear. Here, we review current methodologies to treat receptor conformational changes in structure‐based docking procedures, and show their impact on the accuracy of docking and scoring. We also discuss pitfalls and limitations of state‐of‐the‐art flexible‐receptor docking strategies and perspectives for their improvement. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 298‐314 DOI: 10.1002/wcms.29 This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods

Illustrations of different types of protein conformational changes. In each figure, two or three crystal structures are superimposed; the flexible parts are shown in different colors (red and green—holo‐structures, blue—apo‐structure) and the rest of protein is gray. (a) Domain movement (left = β‐glucosyltransferase): 1jg6 and 1jej; (right = guanylate kinase): 1ex7 and 1ex6. (b)Terminal helix motion (estrogen receptor‐α: 1a52, 1r5k, and 2zbs). (c)Helix unwinding (HSP90: 1uyf and 2ior). (d)Loop motion (dihydrofolate reductase: 1ra2 and 1rx2). (e)Side chain rotation (α‐thrombin cocrystallized with different ligands—1vr1, 1a3b, and 1bhx).

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Comparison of the enrichment factor in the ligands ranking in the top 1% of all ligands in the DUD database (http://blaster.docking.org/dud/) for 12 pharmaceutically relevant receptors comparing rigid‐docking (a, Reprinted with permission from Huang et al. Copyright 2006 American Chemical Society; b, Reprinted with permission from Ref 26. Copyright 2008 American Chemical Society.) and flexible‐docking (Reprinted with permission from Ref 26. Copyright 2008 American Chemical Society.) protocols.

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Schematic representation of a docking procedure based on ensemble docking and including induced‐fit at the final simulation step. (Reprinted with permission from Ref 5. Copyright 2008 Elsevier Ltd.)

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Scoring function used in FLIPDock. (Reprinted with permission from Ref 86. Copyright 2007 Wiley‐Liss, Inc.)

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Illustration of the averaged protein structure method. (Reprinted with permission from Ref 60. Copyright 2004 American Chemical Society.)

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Illustration of different representations of receptor flexibility in docking protocols (see sidebar).

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