On the origins of drug polypharmacology

The ability of small molecules to interact with multiple proteins is commonly referred to as polypharmacology. The now widely accepted polypharmacology of drugs is of particular interest for human health as it has implications beyond therapeutic efficacy, from anticipating adverse drug reactions to identifying potential repurposing opportunities. There have been a number of studies relating the extent of drug polypharmacology to the physicochemical properties and fragment composition of the drug itself, but also to the protein family and distant binding site similarities of the drug's primary target. Taken together, all these observations lead to speculate that the origins of drug polypharmacology may lie at the heart of protein evolution and that polypharmacology may just be a reminiscent signature of some of the mechanisms of adaptation that primitive biological systems developed to increase the chances of survival in a highly variable early chemical environment.