Chain A of one of the structures has been used for the current study. The missing residues in the A-loop are constructed by ModLoop . All water molecules in the pdb file are retained. There are three phosphorylated tyrosine residues in the x-ray structures; they are phosphorylated as well in the simulations. The compounds were docked with the protein using the OpenEye Posit method , drawing on information from the bound ligands to improve pose prediction. All the compounds share the same binding pose at the ROS1 binding site, forming one hydrogen bond with the hinge residue (Figure ). Preparation and setup of the simulations were implemented using the BAC (binding affinity calculator) , including parametrization of the compounds, solvation of the complexes, electrostatic neutralization of the systems by adding counterions and generation of configurations files for the simulations. Protein parameters were taken from the standard Amber force field for bioorganic systems (ff14SB) . Ligand parameterizations were produced using the general Amber force field 2 (GAFF2). The partial charges of the compounds were generated using AM1-BCC method which had been suggested to be preferable compared with the RESP method .