In summary, empirical and semiempirical methods have demonstrated variable performance for ligand-pocket model systems in QUID, yielding a MAE of about 1 kcal/mol or higher and exhibiting a tendency to underbind. In contrast, among the many DFT methods examined, PBE0+MBD and PBE0+D4 proved most effective in capturing the complex QM effects contributing to E int calculations, while PBE0+XDM also showed excellent performance as a pairwise dispersion method. These findings enhance our understanding of the applicability and limitations of the various investigated computational methods.