title: Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors.
abstract: Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Bo
authors.initials: B
authors.lastname: Wan
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D012399:Rotation; D013816:Thermodynamics; D014584:User-Computer Interface; D014867:Water
chemical_list: D047428:Protein Kinase Inhibitors; D014867:Water; D011494:Protein Kinases