In recent years, far more detailed computational methods of estimating protein-small molecule binding free energies that had been under development for decades have been widely adopted, due to their improved accuracy and the dramatic acceleration of simulations by the use of graphics processor units (GPUs) . Most widely used are relative binding free energy (RBFE) calculations , which yield the difference betweeen the binding free energies of two compounds by computing the free energy change of artificially, or alchemically, transforming one compound to the other in the binding site and in the bulk solvent . The alchemical compound transformations in RBFE methods work particularly well when the two compounds being compared are chemically similar. As a consequence, RBFE methods are well suited for use in the hit-to-lead and lead-optimization stages of drug discovery , because these stages typically involve explorations within a single congeneric series of compounds; i.e., a series of compounds that are chemically similar to each other. Good results have been obtained in retrospective benchmarks and in prospective industry applications .