Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.

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.

Covalent bonding can lead to potencies and ligand efficiencies that are either exceptionally high or, for irreversible covalent interactions, even essentially infinite. Covalent bonding thus allows high potency to be routinely achieved in compounds of low molecular mass, along with all the beneficial pharmaceutical properties that are associated with small size.

Covalent inhibitors can be designed to target a nucleophile that is unique or rare across a protein family. Thereby ensuring that covalent bond formation cannot occur with most other family members. This approach can lead to high selectivity against closely related proteins because although the inhibitor might bind transiently to the active sites of such proteins, it will not covalently label them if they lack the targeted nucleophilic residue in the appropriate position.

The restoration of pharmacological activity after covalent irreversible inhibition requires re-synthesis of the protein target. This has important and potentially advantageous consequences for drug pharmacodynamics in which the level and frequency of dosing relates to the extent and duration of the resulting pharmacological effect.

Covalent inhibitors can be used to assess target engagement which can sometimes be used pre-clinically and clinically to assess the relationship between dose of drug and efficacy or toxicity. This approach was used for covalent Btk inhibitors pre-clinically and clinically to understand the relationship between dose administered and efficacy in animal models of arthritis and target occupancy in a clinical study of healthy volunteers.

The design of covalent drugs requires careful optimization of both the non-covalent binding affinity (which is reflected in K_i) and the reactivity of the electrophilic warhead (which is reflected in k₂).