To measure its performance as a virtual screening tool, we evaluated ROSHAMBO in terms of its ability to distinguish the known active ligands from the decoy molecules across each one of the DUDE-Z targets, using the ComboTanimoto score to rank compounds. We measure the number of active molecules retrieved by screening only small percentages of top-scoring compounds for each target, shown in Figure . As described above, we used RDKit to generate up to 60 conformers per molecule. Our ROSHAMBO workflow then used PAPER (initialization mode 7) to measure overlaps, and computed similarity scores using the second-order analytic approximation shown by Equation 9 in the Supplemental Information.