Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

• High potencies and prolonged effects achievable with covalent drugs may result in less frequent dosing and improved therapeutic margins for patients.
• Covalent inhibition can dissociate drug pharmacodynamics from pharmacokinetics.
• Covalent drugs may have reduced risk of developing drug resistance.
• Approvals in recent years suggest that covalent drugs are continuing to make impacts on human health.

Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.