González Bello, Concepción2018-07-022018-07-022016-01-07González-Bello, C. (2016). Designing Irreversible Inhibitors-Worth the Effort?. Chemmedchem, 11(1), 22-30. doi: 10.1002/cmdc.2015004691860-7179http://hdl.handle.net/10347/16926This is the peer-reviewed version of the following article: González-Bello, C. (2016). Designing Irreversible Inhibitors-Worth the Effort?. Chemmedchem, 11(1), 22-30, which has been published in final form at https://doi.org/10.1002/cmdc.201500469. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingDespite the unquestionable success of numerous irreversible drugs that are currently in clinical use, such as acetylsalicylic acid (Aspirin) and penicillin, the number of such approved drugs is much lower than that of noncovalent drugs. Over the years, the potential off‐target effects of these types of compounds have been the primary concern that has hampered their development. However, their remarkable advantages over noncovalent drugs and a better analysis of the risks have decreased the widespread skepticism surrounding them. The design of irreversible inhibitors is a challenge, particularly considering that in some cases their efficacy is due to complex and unexpected mechanisms of action. In this review the main advantages of irreversible inhibition are summarized, and the complexity of certain covalent modification mechanisms is highlighted with selected exampleseng© 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingCovalent catalysisEfficiencyIrreversible inhibitionSelectivityToxicityjournal article10.1002/cmdc.2015004691860-7187open access