Most of the natural compounds at the top of these hit lists feature a limited number of hydroxy or oxo groups, alongside relatively large apolar regions. Their low-energy QM conformations appear to be advantageous in forming strong dispersion interactions. This general trend holds true for the dkoes hit list as well, even though the specific top compounds and targets differ between the two scoring functions. . The Approximate Binding Free Energy is calculated by the sum of the intermolecular interaction energy between the given ligand and the protein using the Vinardo scoring functions and the ab initio conformational strain energy calculated by the QFConfsearchDFT application using DFT-D4 with rev-SCAN functional and def2-TZVP basis set. . The Approximate Binding Free Energy is calculated by the sum of the intermolecular interaction energy between the given ligand and the protein using the dkoes scoring functions and the ab initio conformational strain energy calculated by the QFConfsearchDFT application using DFT-D4 with rev-SCAN functional and def2-TZVP basis set.