Shape-based molecular similarity approaches have been established as important and popular virtual screening techniques. At present, the highly optimized screening platform ROCS (Rapid Overlay of Chemical Structures) is considered the de facto industry standard for shape-based, ligand-centric virtual screening. It uses a Gaussian function to define molecular volumes of small organic molecules. The selection of the query conformation is less important, rendering shape-based screening ideal for ligand-based modeling: As the availability of a bioactive conformation for the query is not the limiting factor for screening — it is more the selection of query compound(s) that is decisive for screening performance.