Inverse Drug Discovery identifies weak electrophiles affording protein conjugates

Traditional biochemical target-based and phenotypic cell -based screening approaches to drug discovery have produced the current covalent and non-covalent pharmacopoeia. Stra-tegies to expand the druggable proteome include Inverse Drug Discovery, which involves incubating one weak organic elec-trophile at a time with the proteins of a living cell to identify the conjugates formed. An alkyne substructure in each organic electrophile enables affinity chromatography-mass spec-trometry, which produces a list of proteins that each distinct compound reacts with. Herein, we review Inverse Drug Dis-covery in the context of organic compounds of intermediate complexity harboring Sulfur(VI)-fluoride exchange (SuFEx) electrophiles used to expand the cellular proteins that can be targeted covalently.