In the history of therapeutics, covalent drugs occupy a very distinct category. While representing a significant fraction of the drugs on the market, very few have been deliberately designed to interact covalently with their biological target. 
Targeted covalent inhibitors have the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. Covalent inhibitors contain specific functional groups, designed to react with a corresponding site in the target, typically an amino acid side chain. The side chain may be part of the catalytic machinery of a target enzyme, or a non-catalytic side-chain located close to the binding pocket. Since covalent bonds are significantly stronger than the non-covalent interactions, the development of covalent inhibitors offers the potential for inhibitors with increased potency over noncovalent analogues. These covalent bonds are often irreversible, and therefore covalent inhibitors offer longer duration of action than reversible inhibitors since the target will remain inhibited until the protein is degraded and then regenerated.
By far the most effort has been directed towards targeting noncatalytic cysteine residues, for example in cysteine proteases and protein kinases, where selectivity for a particular member of a protein family can be challenging. The appeal of cysteine is due in part to its relatively low abundance in proteins, and its high nucleophilicity. The thiolate form of cysteine has been shown to be capable of forming covalent bonds with covalent warheads spanning a wide range of reactivity, with Michael acceptors being key examples. 
 S. De Cesco, J. Kurian, C. Dufresne, A. K. Mittermaier, and N. Moitessier, “Covalent inhibitors design and discovery,” Eur. J. Med. Chem., vol. 138, pp. 96–114, 2017, doi: 10.1016/j.ejmech.2017.06.019.
 R. Lonsdale and R. A. Ward, “Structure-based design of targeted covalent inhibitors,” Chem. Soc. Rev., vol. 47, no. 11, pp. 3816–3830, 2018, doi: 10.1039/c7cs00220c.
 M. Gehringer and S. A. Laufer, “Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology,” J. Med. Chem., vol. 62, no. 12, pp. 5673–5724, 2019, doi: 10.1021/acs.jmedchem.8b01153.
 P. A. Jackson, J. C. Widen, D. A. Harki, and K. M. Brummond, “Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions,” J. Med. Chem., vol. 60, no. 3, pp. 839–885, 2017, doi: 10.1021/acs.jmedchem.6b00788.
 T. Barf and A. Kaptein, “Irreversible protein kinase inhibitors: Balancing the benefits and risks,” J. Med. Chem., vol. 55, no. 14, pp. 6243–6262, 2012, doi: 10.1021/jm3003203.
 R. A. Bauer, “Covalent inhibitors in drug discovery: From accidental discoveries to avoided liabilities and designed therapies,” Drug Discov. Today, vol. 20, no. 9, pp. 1061–1073, 2015, doi: 10.1016/j.drudis.2015.05.005.
Medicinal and Computational Chemistry Dept., ChemDiv, Inc.
12760 High Bluff Dr, San Diego, CA, 92130
Phone: + 1 916 234 0888
Fax: +1 858 794 4931
You can buy this library or customize your own library from our discovery collection of 1 600 000 compounds and 60 000 building blocks.