In the past decade, structure-based methods have become widespread in drug discovery thanks to a powerful combination of improvements in force field accuracy , methods, software and hardware, including GPUs 2 . Due to the extremely limited value of virtual screening methods, binding affinity calculation methods offer a promising alternative. If implemented correctly, they are far more accurate than simple docking scores as they also capture the dynamics of protein-ligand binding including conformational changes and solvation effects. But they are far more computationally expensive and require more wall clock time to compute. The accurate and reliable prediction of protein-ligand binding affinities can evidently play an important role in the drug discovery process.