For protein targets BACE1, CDK2, and thrombin, all compound SMILES strings in the files actives_final.ism and decoys_final.ism were downloaded from the DUD-E website . The actives are compounds with effective affinities of 1 µM or better, and the decoys are automatically generated compounds with molecular properties similar to those of the actives of the respective targets. These properties include molecular weight, water-octanol partition coefficient, number of rotatable bonds, numbers of hydrogen bond acceptors and donors, and net charge. However, the decoys are quite different in chemical structure from the actives, so the decoys are unlikely to be active against the target . Targets BACE1, CDK2, and thrombin are associated respectively with 283, 474, 461 actives and 18100, 27850, and 27004 decoys. The compound SMILES strings were imported to Maestro [29] and processed using Ligprep . Alternate protonation states, tautomeric states, and stereoisomers were generated to include all possible chemical forms of the compound, along with an Epik penalty term, a quantitative estimate of the relative stability of each form. Stereoisomers were generated because some compounds have undefined stereocenters in their SMILES. We assumed that such compounds were racemic mixtures, so the affinity of the stereoisomer which binds the best should be a good approximation to the binding affinity of the mixture. For CDK2, protonation states were generated for the pH range 5 to 9. For thrombin, protonation states were generated for the pH range 5.5 to 9.5. For BACE1, ligand protonation states were generated for pH values down to 0, to account for the lower experimental pH of 4.5; and up to 10, to allow for the possibility of relatively large upward shifts of ligand pKa due to the two charged aspartates in the catalytic site.