The MMPBSA and thermodynamic scores for the top 87 hits in our screen correlated strongly (r 2 =0.85). Given that many of the top-ranked molecules are conformationally flexible, binding energy penalties due to ligand entropy are likely to be significant. A substantial correlation was found between the Vina scores and the binding energies from MMPBSA and the thermodynamic cycle, important because of the different ways these algorithms treat ligand entropy .