Docking and scoring methods have long been used to assist with hit identification and optimization in computer-aided drug design (CADD) . More recently, efforts to improve the reliability of CADD methodologies have gone beyond qualitative docking and scoring towards quantitative modeling via molecular simulations, which can be used to estimate a variety of physical properties of interest . In this area, predictions of protein-ligand binding free energies have gained much attention for a few decades for their potential to help accelerate small-molecule drug discovery , but have received increasing attention recently as this potential begins to be realized . The long-term goal is to use computational techniques to aid and direct small molecule design to more rapidly and efficiently produce new therapeutics . Right now, much discovery works via a slow cycle of experimental trial and error, but accurate enough free energy methods could dramatically accelerate early stage discovery .