Cysteine Targeted Covalent Library consists of a total of 41,378 compounds. Covalent drugs play a unique role in the field of therapeutics, although only a small number have been intentionally designed to interact covalently with their biological targets, despite being a significant portion of the drugs available on the market.
Targeted covalent inhibitors offer the potential to enhance the potency and selectivity of small molecule inhibitors by utilizing reactive functional groups that covalently bind to specific sites in a target. These inhibitors contain specific functional groups that are designed to react with specific sites, typically amino acid side chains, in the target molecule. These side chains may be involved in the catalytic machinery of an enzyme or may be non-catalytic side chains located near the binding pocket. The formation of covalent bonds is much stronger than non-covalent interactions, which allows for the development of inhibitors with increased potency compared to non-covalent analogues. Moreover, the covalent bonds formed are often irreversible, resulting in a longer duration of action compared to reversible inhibitors, as the target remains inhibited until the protein is degraded and regenerated.
Interestingly, the majority of research efforts in the field have focused on targeting non-catalytic cysteine residues, particularly in cysteine proteases and protein kinases. Achieving selectivity for a specific member of a protein family can be challenging in these cases. Cysteine is appealing as a target due, in part, to its relatively low abundance in proteins and its high nucleophilicity. The thiolate form of cysteine has demonstrated the ability to form covalent bonds with a variety of covalent warheads, including Michael acceptors, which are key examples of reactive groups used in targeting cysteine residues.
