Background: Promiscuity of drugs and targets plays an important role in drug-target prediction, ranging from the explanation of side effects to their exploitation in drug repositioning. A specific form of promiscuity concerns drugs, which interfere with protein–protein interactions. With the rising importance of such drugs in drug discovery and with the large-scale availability of structural data, the question arises on the structural basis of this form of promiscuity and the commonalities of the underlying protein–ligand (PLI) and protein–protein interactions (PPI). Research design and methods: The authors applied the protein–ligand interaction profiler, PLIP, to experimental and predicted structures and characterize drugs in clinical trials, which target PPI. Results: PPIs generally involve more non-covalent interactions than PLI with overlapping interaction patterns and key binding site residues. In contrast to experimental structures, predicted structures fall short in accurately capturing interaction details at the interface. Conclusion: Taken together, our analysis shows that PPIs and PLIs have sufficient commonalities to merit future work into computational screenings for drugs targeting PPIs. It will be key to further improve structure prediction, specifically for binding site details.