DFG-in and DFG-out homology models of TrkB kinase receptor: Induced-fit and ensemble docking

Kinases from the Trk family are important for the regulation of development and for the correct functioning of the neural system. Deregulation (over-expression) of Trks leads to survival and proliferation of different human cancers. Therefore, development of inhibitors for Trks that can disrupt the signal pathway of Trks could lead to cure against cancer as well as to nociception. Homology models built by YASARA have been used as targets for docking various libraries of known Trk inhibitors. The receptor plasticity was compensated with induced fit docking and/or ensemble docking. It was determined that DFG-in and DFG-out conformational states of TrkB kinase must be taken into account in order to get more reasonable relationships between the docking score and the activity measured by pIC50 for the corresponding ligands.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (279 K)Download as PowerPoint slideResearch highlights▶ DFG-in and DFG-out models of TrkB have been built by YASARA. ▶ IFD may be useful with some caveat, for the classification of kinase inhibitors. ▶ Interesting examples of binding Trk inhibitors to DFG-in/out models are exposed. ▶ Identification of Trk ligands from large combined database with ensemble docking.