ReviewPost screenDesigned covalent allosteric modulators: an emerging paradigm in drug discovery

•Covalent drugs offer advantages over conventional noncovalent drugs.•Covalent allosteric modulators have higher selectivity than covalent drugs.•We review the design of covalent allosteric modulators with successful examples.•Potential strategies for future design of covalent allosteric modulators are discussed.•Covalent allosteric modulators provide a new avenue to drug discovery.

Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable tool in drug discovery. Here, we review the recent advances in the design of covalent allosteric modulators with an emphasis on successful examples. A broad spectrum of protein targets capable of being modulated by them reflects the prevalence of this strategy. We also discuss the challenges and future directions in the development of covalent allosteric modulators.