As shown in Figure , RF(SQM, PLEC, descr) and SQM-ML have significantly higher performance than the null models, but also than the other RF variants including the SQM terms. They are also better than the original PM6/COSMO and marginally better than Glide SP. Thus, the null hypothesis is rejected, and we conclude that the inclusion of SQM terms is necessary to improve the scoring, which is also corroborated by the feature importances calculated on the cross-validation sets (Figure ). More specifically the combination of all three feature classes is better than any pairwise combination thereof. Moreover, the The description in parenthesis denotes the part of the system that was subsequently optimized on the PM6/COSMO level. SQM(ligand atoms)*: same as SQM(ligand atoms), but docking poses with extremely low or extremely high Eint were discarded (read about outlier removal in Methods). C) Distribution of interaction Energies when i) only ligand, ii) ligand and all protein residues within 4 Å, iii) ligand and all protein residues within 6 Å are included in the SQM part. D) Distribution of time per complex needed for optimization and scoring in cases i), ii) and iii). The performance per receptor of SQM-ML, SQM, and Glide SP is illustrated in Figure , while the rest of the RF models are in Figure . Both PM6/COSMO and Glide SP have case-specific accuracy, with the former being better in all sets but 4 (SARS-HCoV, GBA, PPARG, GR). At least in three sets, SIRT2, SARS, and GBA, both PM6/COSMO and Glide SP behave like random classifiers. This is not the case with SQM-ML, which in SIRT2 and GBA sets demonstrates remarkable improvement in accuracy. Moreover, in 7 out of 12 sets SQM-ML is better or equally accurate than Glide, while in 10 out of 12 is better or equally good than its parent SF, PM6/COSMO. SQM-ML exhibits slightly weaker classification power than PM6/COSMO only in PPARG and GR (possible reasons are discussed later), with the latter not being statistically significant according to the SEM. In general, SQM-ML offers more stable scoring and generalizability than PM6/COSMO and Glide SP across all receptors of the external test sets.