A Medicinal Chemistry Perspective on FDA-Approved Small Molecule Drugs with a Covalent Mechanism of Action

Covalent modification of disease-driving proteins as a therapeutic strategy has experienced a well-documented resurgence since 2010. However, the earliest FDA approval dates for covalent drugs are in the 1940s, although the covalent mechanism of action may not have been known at the time. This article discloses a data set of all FDA-approved small molecule drugs acting via a covalent mechanism of action, annotated by indication, biological target, reactive group on the drug, biological reactive partner (i.e., amino acid residue, cofactor, etc.), chemical reaction mechanism, bioactivation requirements, key references, and reversibility profile. We discuss these data in the context of addressing key questions posed by the Merck Discovery Chemistry community when considering a chemical series with a covalent mechanism of action.