The present ABFE calculations outperform docking calculations for both Tiers of ligands on all three targets, as assessed from the areas under the curve of their respective receiver-operating characteristic curves (Figure ). Across all six tests -three targets, each with two tiers -the AUC increases by an average of 0.16 (0.67 to 0.83) on going from docking to ABFE, with BACE1 improving most and thrombin least. Thus, a central conclusion of this work is that ABFE calculations can yield greater enrichment of actives over decoys in the context of virtual compound screening. Histograms of the computed ABFEs for the actives and decoys in all six tests detail the negative (favorable) displacement of the actives' ABFE distributions relative to those of the decoys (Figure ). The analogous plots for docking scores in SI show smaller separations between the actives and decoys. However, there is still significant overlap between the two ABFE distributions in all six cases, as some decoys are assigned quite favorable binding free energies.