Absolute binding free energy (ABFE) methods are technically related to RBFE methods, but differ in that they directly yield the standard binding free energy of a given compound for the protein or receptor of interest. This quantity is computed from the reversible work of decoupling the ligand from the binding site and recoupling it with bulk solvent, in effect leaving the free ligand at standard 1 M concentration . The decoupling and recoupling steps can be carried out by alchemical pathways or by physical pathways . Importantly, ABFE methods can be applied directly to collections of compounds that are not chemically similar to each other. As a consequence, ABFE calculations might be suitable for virtual screening of diverse compounds , except that they are much too slow to process an entire compound library. Thus, ABFE calculations are perhaps best used to refine initial docking results by providing more accurate discrimination between active and inactive compounds within focused sets of diverse compounds with high docking scores. However, a fullfledged trial of ABFE as a refinement step in virtual compound screening has not yet been described, despite strong advances in ABFE implementations . This delay may stem from the challenges associated with these calculations, such as protein conformational changes between bound and apo states, and the need to predict ligand binding poses .