Inspecting the five least similar, experimentally-confirmed hits from the RF-C model (Table S9) and the Similarity Baseline (Table ) illustrates these differences. The maximum Tanimoto distance from RF-C is 0.57 compared to a maximum distance of 0.32 for the Similarity Baseline. The Similarity Baseline is based solely on chemical similarity to the known actives, so its prioritized compounds are mostly minor variations on these actives. In contrast, the RF-C model uses information from both active and inactive training instances to rank compounds. Although there are common substructures with the known actives, the AMS hits from RF-C are more distant overall. The distance between the prioritized AMS compounds and their nearest known active was not predictive of whether the prioritized compound would be active. The distance distributions for AMS actives and inactives were similar when considering all 1,024 ordered compounds (Figure ), the compounds selected by the RF-C model (Figure ), or the compounds selected by the Similarity Baseline (Figure ).