text: Over the last 100 years covalent drugs have made a major impact on human health and have been highly successful drugs for the pharmaceutical industry. These inhibitors react with their target proteins to form a covalent complex in which the protein has lost its function. The majority of these successful drugs, which include penicillin, omeprazole, clopidogrel, and aspirin were discovered through serendipity in phenotypic screens.
  However, key changes in screening approaches, along with safety concerns, have made pharma reluctant to pursue covalent inhibitors in a systematic way (Liebler & Guengerich, 2005). Recently, there has been considerable attention to using rational drug design to create highly selective covalent inhibitors called targeted covalent inhibitors. The first published example of a targeted covalent drug was for the EGFR kinase. But this has now broadened to other kinases and other protein families. Aside from small molecules, covalent probes are also being derived from peptides or proteins. By incorporation of a reactive group into a binding peptide or protein via posttranslational chemical modification or as an unnatural amino acid, a target protein can be conjugated specifically via proximity-induced reaction.