Abstract | One of the current challenges in docking studies is the inclusion of receptor flexibility. This is crucial because the binding sites of many therapeutic targets sample a wide range of conformational states, which has major consequences on molecular recognition. In this paper, we make use of very large sets of X-ray structures of cyclin dependent kinase 2 (CDK2) and heat shock protein 90 (HSP90) to assess the performance of flexible receptor docking in binding-mode prediction and virtual screening experiments. Flexible receptor docking performs much better than rigid receptor docking in the former application. Regarding the latter, we observe a significant improvement in the prediction of binding affinities, but owing to an increase in the number of false positives, this is not translated into better hit rates. A simple scoring scheme to correct this limitation is presented. More importantly, pitfalls inherent to flexible receptor docking have been identified and guidelines are presented to avoid them. |