For the examples reported in Table , it can be seen that the alignments produced by the three combo scores are generally more consistent in terms of chemistry (in particular with regard to the orientation of chemical features) than the alignments produced by the ShapeTanimoto score. However, the FitTverskyCombo score failed to identify the target of interest for many CSMs due to its emphasis on matching the knowledge base molecule (substructure). More specifically, the FitTverskyCombo score assigns high scores to many small knowledge base molecules, thus giving rise to a high false-positive prediction rate. In contrast, the ShapeTanimoto score often failed because of its disregard of chemistry, which is reflected by alignments that lack the matching of chemical features. Queries marked with a "*" are macrocyclic compounds. Among the 350 queries investigated in this work, we identified eleven compounds (six of them are macrocyclic compounds) for which their target was ranked within the top-10 positions out of 3642 targets, despite being structurally dissimilar from any ligands (non-CSMs) recorded in the knowledge base (Tanimoto coefficient lower than 0.18). As shown in Table , most of the alignments produced by ROCS for the eleven compounds are not only plausible and sensible from a chemistry point of view, but also visually easily interpretable, thanks to the hard Gaussians used by ROCS for chemical features (color), which cause a lock-in of the alignment on hydrogen bond donors and acceptors.