A)The NMR (Nuclear Magnetic Resonance) structures of Abl1 kinase overlay, comparing the activation loop (A-loop) in the active DFG-in state (red, PDB: 6XR6) with the classical DFG-out state (blue, PDB: 6XRG). Type I inhibitors target the active DFG-in state, where the DFG motif adopting the DFG-in configuration and the A-loop adopting the “extended” configuration, while type II inhibitors target the classical DFG-out state, where the DFG motif adopting the DFG-out configuration and the A-loop is “folded”. The distance between CB atoms of residue N98 (grey bead) and residue R162 (red/blue bead) in Abl1 kinase serves as an order parameter here to illustrate the location of the A-loop. The dashed black block emphasizes the different configurations of the DFG motif in this two states. B) The Dunbrack definition for DFG motif configuration is employed here. The Dunbrack space is delineated by two order parameters: D1=dist(F158-CZ, M66-CA), D2=dist(F158-CZ, K47-CA). C) or D) The docking poses with the lowest ligand RMSD for 4 known kinase inhibitors targeting the Abl1 or DDR1 kinase AF2 structure, generated by Glide XP. Co-crystallized structures are shown as light-cyan cartoons (proteins), green sticks (ligand) and magenta sticks (DFG motif). Docking poses are shown as light-gray cartoons (proteins), gray sticks (ligand) and blue sticks (DFG motif). Comparing with type I inhibitors, AF2 structures of protein kinases fail to dock with type II inhibitors.