Similarity Calculations. After alignment, ROSHAMBO ranks compounds based on standard 3D similarity scores, specifically Tanimoto (Equation ) and Tversky (Equation ) scores. When comparing query compound a and dataset compound b, these scores are defined as: For all of these scores, the user can specify the method used to calculate the overlaps. The default is the second-order analytic approximation shown in Equation 9 in the Supplemental Information, the same method used in the overlap optimization itself. The user can further specify the value of Gaussian or proxy cutoffs. Alternatively, one can also increase the accuracy of the approximation by increasing the order. For example, a third-order approximation corresponds to Equation 14 in the Supplemental Information. For the benchmarking done in this work, we used a second-order approximation.