Targeted Covalent Inhibitors for Drug Design
Corresponding Author
Prof. Thomas A. Baillie
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA, 98195-7610 USA
Search for more papers by this authorCorresponding Author
Prof. Thomas A. Baillie
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Box 357610, Seattle, WA, 98195-7610 USA
Search for more papers by this authorGraphical Abstract
In a bind: Targeted covalent inhibitors (TCIs), such as HKI-272 (shown in the picture in complex with a protein), first form a reversible association and then a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. This can offer benefits such as high potency and extended duration of action, and new approaches can limit the risk of serious adverse reactions.
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.
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