In a previous study using the PDE2 system, the ligands were classified as small or large based on the size of substituents attached to the scaffold. Ligands with hydrogen or methoxy group as substituents were called 'small' and those with larger substituents were considered 'large'. It was shown that FEP+ predicted ∆∆G values for transformations from small-tosmall (s2s) ligands and large-to-large (l2l) ligands were relatively more accurate (MUEs less than 1 kcal/mol) compared to those from small-to-large (s2l) ligands (MUE over 2 kcal/mol).