In all the cases initialization of the models (iteration 0) was based on the weighted random selection. Namely, the ligands were selected with the probability inversely proportional to the number of similar ligands in the dataset. Ligands were considered similar if after a t-SNE embeding 20 they fell within the same bin of a 2D histogram (the square bins of the 2D histogram had a side length of one unit in the t-SNE space). The embedding was constructed from the ligands' 2D features (constitutional and graph descriptors as well as MACCS and BCUT2D 37 fingerprints) using the full ligands for the retrospective library and only the Rgroups for the prospective library.