Covalent-Allosteric Inhibitors: Do We Get the Best of Both Worlds?

Covalent-allosteric inhibitors (CAIs) may achieve the best of both worlds: increased potency, long-lasting effects, and reduced drug resistance typical of covalent ligands, along with enhanced specificity and decreased toxicity inherent in allosteric modulators. Therefore, CAIs can be an effective strategy to transform many undruggable targets into druggable ones. However, CAIs are challenging to design. In this perspective, we analyze the discovery of known CAIs targeting three protein families: protein phosphatases, protein kinases, and GTPases. We also discuss how computational methods and tools can play a role in addressing the practical challenges of rational CAI design.