Conventional small molecule drug-discovery approaches target protein pockets. However, the limited number of geometrically distinct pockets leads to widespread promiscuity and deleterious side-effects. Here, the idea of COmposite protein LIGands (COLIG) that interact with each other as well as the protein within a single ligand binding pocket is examined. As a practical illustration, experimental evidence that E. coli Dihydrofolate reductase inhibitors are COLIGs is presented. Then, analysis of a non-redundant set of all holo PDB structures indicates that almost 47–76% of proteins (based on different sequence identity thresholds) can simultaneously bind multiple, interacting ligands in the same pocket. Moreover, most ligands that are either Singletons and COLIGS bind at the bottom of ligand binding pocket and occupy 30% and 43% of the volume of the bottom of the pocket. This suggests the use of COLIGs as a potential new class of small molecule drugs.