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Receptor flexibility in small-molecule docking calculations



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