Ligand binding poses were then refined by molecular dynamics simulations in vacuum. First, a hybrid topology between the reference inhibitor and each ligand was constructed with pmx and the coordinates of the largest common substructure were restrained with a force constant of 9000 kJ/mol/nm 2 . Next, the energy of the protein and reference inhibitor system was minimized. Finally, the reference inhibitor was morphed into the ligand following the hybrid topology while simultaneously lowering the temperature from 298 K to 0 K in a 10 ps simulation. Ligand coordinates from the final frame were treated as the binding pose and used to construct both the ligand representations for machine learning and as starting ligand coordinates for the relative binding free energy calculations.