Abstract
Covalent inhibitors have several attractive features as chemical probes and drugs. Historically, the common way to develop covalent inhibitors was to derivatize a known non-covalent inhibitor or substrate. In recent years, however, covalent fragment screening is establishing itself as an alternative, perhaps more suitable for challenging targets, with no previous chemical matter. Fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, and offer a very direct and general binding assay via mass spectrometry. All the while, they retain a high probability of binding to target proteins and efficient coverage of chemical space due to their small size. As this method is increasingly utilized, insights were gained regarding the most suitable electrophiles for covalent fragment libraries, methods to deal with intrinsic reactivity and notable successful applications were reported. Here we review recent efforts in this field in an attempt to enable broader and more efficient use of covalent fragment screening.