We have developed a method that uses energy landscapes of unbound and bound ligands to compute reorganization free energies for end-point binding free-energy calculations. The method is applied to our previous simulations of fentanyl derivatives bound to the μ opioid receptor in different orientations. Whereas the mean interaction energy provides an ambiguous ranking of binding poses, interaction entropy and ligand reorganization strongly penalize geometric decoys such that native poses observed in CryoEM structures are best ranked. The binding pose of fentanyl is driven by the interaction entropy. Binding of (3R,4S)-lofentanil is favored over that of (3S,4R)-lofentanil, largely because binding the latter requires the ligand to reorganize to a conformation with high free energy. The same phenomenon is predicted to favor the binding orientation of carfentanil. Our method can be applied to other end-point binding free-energy calculations for a relatively low cost of sampling the unbound ligand. Source code is included in the Supporting Information.