biostudies-literatureMartin JSWellcome Trust2066-2074https://www.ebi.ac.uk/biostudies/studies/S-EPMC6538824biostudies-literatureUnknown27(10)Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine Bioorganic & medicinal chemistryCharacterising covalent warhead reactivity.PMC6538824203134/Z/16/ZMartin JSMacKenzie CJGilbert IHFletcher DfalseCharacterising covalent warhead reactivity.Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine 2019-01-01T00:00:00Z2019 May2025-04-20T03:25:10.947Z2019-07-01T13:56:14ZS-EPMC65388243097550110.1016/j.bmc.2019.04.002