PAPER, the software ROSHAMBO uses to measure optimal 3D overlap, was previously benchmarked against ROCS, the industry standard for 3D molecular shape alignment and similarity scoring. The authors found that both softwares performed near identically as shape-based virtual screening tools on the DUD data set. Here, we further benchmark ROSHAMBO performance on the publicly-available DUDE-Z dataset, a recently enhanced version of the popular DUD-E dataset 37 used to validate many computational chemistry and cheminformatic workflows. ROSHAMBO, as a virtual screening tool, provides significant active compound enrichment on many pharmaceutically-relevant target classes, and proves superior in terms of speed and performance to another open-source shape similarity tool, Shape-it. ROSHAMBO also easily scales across GPUs and CPUs to allow users to run ROSHAMBO at industrial scale.