With increasing confidence levels, the number of molecules predicted as "highly active" decreased (Fig. ), a documented effect of ensemble voting . None of the molecules from the focused virtual library was predicted as "highly active" with all 100 votes. Forty-seven de novo designs were predicted as highly active, with 99 votes. Among these top-ranked molecules, 64% featured a new atom scaffold and 62% featured a new graph scaffold with respect to the finetuning set . Higher confidence was reflected in the increased substructure similarity of the predicted actives to the molecules of the fine-tuning set, as captured by the Tanimoto index computed on Morgan fingerprints (Fig. ) . In line with the chemical similarity principle , this observation suggests that there is a greater chance of identifying active molecules when the number of votes is high. The five most dissimilar molecules among the top-ranked molecules had a similarity to their respective nearest neighbors of the fine-tuning set, ranging from 53% to 58% (Fig. ). The closest molecules of the fine-tuning set have a similarity ranging between 77% and 100%, meaning that one molecule of the fine-tuning set was re-created by the CLM, although with a different stereochemistry (Fig. ), a structural feature that is not captured by Morgan fingerprints. This result highlights the potential of the approach to explore both closely related molecules to known bioactives, e.g., for structure-activity relationship studies or hit-to-lead expansion, as well as more structurally innovative compounds for "scaffold hopping". The solid line represents the mean value, with the shaded area representing the standard deviation. c, Top-ranked designs (99/100 votes) selected with the most distant nearest neighbor, whose similarity is indicated below the structure ("Most similar") in the fine-tuning set. The atom ("Atom scaffold") and graph ("Graph scaffold") scaffold novelty of the structure with respect to the fine-tuning set is indicated below each structure ("Yes": new, "No": not new). d, Top-ranked designs (99/100 votes) selected with the closest nearest neighbor in the fine-tuning set.