Unveiling the full potential of flexible receptor docking using multiple crystallographic structures.
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.
Barril
Xavier
X
Vernalis (R&D), Granta Park, Abington, Cambridge CB1 6GB, UK. x.barril@vernalis.com
Morley
S David
SD
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D030562:Databases, Protein; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D018841:HSP90 Heat-Shock Proteins; D011956:Receptors, Cell Surface; D011955:Receptors, Drug; D000255:Adenosine Triphosphate; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2