title: Designing Irreversible Inhibitors--Worth the Effort?
abstract: Despite 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 examples.
authors.affiliation: Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, calle Jenaro de la Fuente s/n, Santiago de Compostela, 15782, Spain. concepcion.gonzalez.bello@usc.es.
authors.forename: Concepción
authors.identifier: http://orcid.org/0000-0001-6439-553X
authors.initials: C
authors.lastname: González-Bello
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D001618:beta-Lactamases; C108449:oxacillinase; D017506:H(+)-K(+)-Exchanging ATPase; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase
keywords: covalent catalysis; efficiency; irreversible inhibition; selectivity; toxicity