• ChEMBL LO datasets: We examined the human protein targets in ChEMBL with the most bioactivity data and chose known drug discovery proteins (avoiding ADMET related proteins for instance) for which experimental 3D protein structures were available. Crystal structures were then retrieved for these proteins from the protein databank filtering to retain only X-ray structures with 2.5 Å or better resolution. Compounds with experimental data were extracted from the ChEMBL database for the specified proteins. The pChEMBL value was used as the activity measure. Overall, the 6 datasets were prepared using docking to augment the size of the dataset as described later. Unlike the prior LO datasets, the increased chemical diversity in the ChEMBL data did not always allow for reliable MCS docking. Instead, we performed constrained docking by specifying simple and well-known key interaction(s) that need to be satisfied, such as the hinge binding motif for the kinase targets, or the interaction with the catalytic aspartates in beta secretase. The details for the datasets are summarized in Table .