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.