Among the four investigated scores, the TanimotoCombo score clearly outperformed all other scores in ranking the targets of CSMs among the top positions of 3642 proteins (Table and The scatter plots in Figure visualize the relationship between scores and ranks obtained for the individual CSM-target pairs. As seen in the figure, a wide range of scores correspond to targets that were appropriately ranked within the top ranks. The correlation between the rank of the target of interest and the score for this CSM-target pair is stronger for the three "combo" scores than for the ShapeTanimoto score. For the ShapeTanimoto score in particular, high scores often do not correspond to high rankings (lack of a tail towards the bottom right corner of the plot, as opposed to the plots for the other scores), indicating a lack of specificity of the approach that is expected to be related to the neglect of chemistry. Figure visualizes the distributions of ShapeTanimoto vs. TanimotoCombo scores (scaled to have identical ranges). It shows that high scores are more frequently observed for the ShapeTanimoto than the TanimotoCombo score, which is plausible because good overlaps of molecular shapes are more likely when chemical features (color) are not taken into account. Because of the emphasis on the coverage of the knowledge base molecule (the substructure), the FitTverskyCombo score is higher than the other scores for most CSM-target pairs. Clearly, this shows that values obtained with different scores should not be directly compared. Moreover, the scores obtained for individual query-target combinations should not be used as a measure of the likelihood of a compound to be active on that target. In other words, the predictions provide an indication of the likelihood of a protein being a target only relative to all other possible targets. A further way of analyzing success rates is on a per-target basis, evaluating the results for query sets (the ten queries) rather than individual queries. For 29 of the 35 targets (83%), the TanimotoCombo score assigned the top rank to the target of interest for at least one of the ten queries (Figure ). For the ShapeTanimoto, RefTverskyCombo and FitTverskyCombo scores, this was only the case for 40%, 49% and 26% of the 35 proteins, respectively. Additional details are provided in Table . For the paired box protein Pax-8, the highest rank obtained with any of the ten queries was 32 (TanimotoCombo score). One of the reasons for failure is the fact that most of the CSMs active on this target are very different from the bioactive non-CSMs in terms of chemistry. They are characterized by long and flexible scaffolds; a minority are macrocyclic (indicated in Figure ).