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.

Automated summary

In this review, we examine the application of Inverse Drug Discovery method using organic compounds of intermediate complexity harboring Sulfur(VI)-fluoride exchange (SuFEx) electrophiles to expand the cellular proteins that can be targeted covalently.