The capacity of shape-based approaches to predict the macromolecular targets of CSMs was explored with ROCS, a leading and widely applied 3D shape-based screening engine. As explained in detail in the Methods section, for the purpose of this study CSMs are compounds that are either macrocyclic and consisting of at least 30 heavy atoms, or non-macrocyclic and consisting of at least 45 heavy atoms. In contrast, non-CSMs are any compounds which consist of 15 to 30 heavy atoms.