title: Targeted Covalent Inhibitors for Drug Design.
abstract: In contrast to the traditional mechanism of drug action that relies on the reversible, noncovalent interaction of a ligand with its biological target, a targeted covalent inhibitor (TCI) is designed such that the initial, reversible association is followed by the formation of a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. Although this approach offers a variety of potential benefits (high potency and extended duration of action), concerns over the possible toxicological consequences of protein haptenization have hindered the development of the TCI concept. Recently, approaches to mitigate the risk of serious adverse reactions to this new class of agent have emerged, thus stimulating interest in the field and leading to authorization of the first cadre of TCIs to be marketed. The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA, 98195-7610, USA. tbaillie@uw.edu.
authors.forename: Thomas A
authors.identifier: 0000-0001-8629-4801
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011494:Protein Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011494:Protein Kinases; D066246:ErbB Receptors
keywords: covalent drugs; drug design; electrophiles; inhibitors; protein modifications