We computed the ROGI based on the 208 PhysChem descriptors available in RDKit as of October 2022 (the rdkit.ML.Descriptors.MoleculeDescriptors.MolecularDescriptorCalculator function). The alternative, based on Morgan fingerprints also computed by RDKit, led to small ROGI values for all MF-PCBA datasets. Furthermore, the ROGI computation is applied to the filtered datasets before setting missing DR values to the minimum pXC50 value. This prevents artificially modifying the ROGI, for example by 'flattening' the activity space. In contrast, all the trained machine learning models use All illustration include the Pearson correlation coefficient (r). Brighter colours correspond to higher R 2 or ∆R 2 values. Plots for the rest of the models are available in Supplementary Information 4 and Supplementary Information 5.