While we have already inspected the chemistry of the predicted high affinity compounds ( Fig 7), it is also interesting to understand what molecules were identified by the models as particularly weak binders. It appears that in the prospective study (Part II), a large fraction of molecules predicted as low affinity binders contained sulfonyl groups (Fig. ). Although alchemical calculations did not find any of the sylfonyl containing ligands to be strong binders, Figure : The strongest binding ligands found, their calculated binding free energies, and binding poses sampled with molecular dynamics. some did reach medium binding affinities of -15 kcal/mol. Thus, sulfonyl should not necessarily be a disqualifying factor for ligand affinity to PDE2. Yet, why does this chemical group dominate the predicted low affinity ligands?