Overall, it is reassuring that all recent DFT approximations yield rather accurate results. Even if some of them underestimate (PBE0+XDM, M06-2X, PBE0+MBD-NL) or overestimate (PBE0+TS) the reference interaction energies on average, the spread of deviations is rather narrow for all DFT methods. On the other hand, both empirical and semiempirical methods show a tendency to underbind, producing larger spreads and exhibiting large outliers. The most prominent outliers are found for CHARMM36 the DFTB3+MBD methods for ∆E int values in ranges from -12.5 kcal/mol to -5 kcal/mol (details in Fig. of the SI) and -7.5 kcal/mol to -4.5 kcal/mol, correspondingly. Examining the DFTB3+MBD outliers-SF1I2, SF3I1, and SF3I3 dimers-reveals that for SF1I2 the strongest interactions are driven by electrostatics, including contributions from a sulfonyl group at the binding site, while the SF3Ix dimers exhibit reactive thiazole groups. It is noticeable that the error distributions of GFN2-xTB (a SE method) and AMBER-GAFF2 (an empirical FF) are quite similar, although GFN2-xTB has a slightly lower average deviation from LNO-CCSD(T). Since GFN2-xTB was partially fitted to CCSD(T) data while AMBER-GAFF was not, this is not surprising.