However, RBFE calculations can become difficult and even intractable when the two compounds of interest are chemically distinct from each other. One reason is that it can become difficult to design an alchemical pathway between the two compounds that affords good numerical convergence . Another reason is that totally different compounds can adopt totally different orientations and conformations, or poses, in the binding site, and obtaining a correct result would require the molecular dynamics (MD) simulations to sample the interconversion of the two ligands' poses. Such interconversions are usually very rare, at least when standard MD is used, because of the steric barrier to ligand motions imposed by the tightly fitted binding site. As a consequence, RBFE calculations are not as well suited to virtual compound screening, and thus are not available as a potential improvement over docking.