Electrophilic warheads in covalent drug discovery: an overview

Covalent drugs have been used for more than hundred years, but gathered larger interest in the last two decades. There are currently over a 100 different electrophilic warheads used in covalent ligands, and there are several considerations tailoring their reactivity against the target of interest, which is still a challenging task.

This review aims to give an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed by targeted residues, mechanism and selectivity, and analyzed through three different datasets including our collection of warheads, the CovPDB database, and the FDA approved covalent drugs. Moreover, the authors summarize general practices that facilitate the selection of the appropriate warhead for the target of interest.

In spite of the numerous electrophilic warheads, only a fraction of them is used in current drug discovery projects. Recent studies identified new tractable residues by applying a wider array of warhead chemistries. However, versatile, selective warheads are not available for all targetable amino acids, hence discovery of new warheads for these residues is needed. Broadening the toolbox of the warheads could result in novel inhibitors even for challenging targets developing with significant therapeutic potential.