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Drugs that act by covalently attaching to their targets have been used to treat human diseases for over a hundred years. However, the deliberate design of covalent drugs was discouraged due to concerns of toxicity and off-target effects. Recent successes in covalent drug discovery have sparked fresh interest in this field. New screening and testing methods aimed at covalent inhibitors can play pivotal roles in facilitating the discovery process. This feature article focuses on computational and biophysical advances originating from our labs over the past decade and how these approaches have contributed to the design of prolyl oligopeptidase (POP) and SARS-CoV-2 3CLpro covalent inhibitors. [ABSTRACT FROM AUTHOR]

In the history of therapeutics, covalent drugs occupy a very distinct category. While representing a significant fraction of the drugs on the market, very few have been deliberately designed to interact covalently with their biological target. In this review, the prevalence of covalent drugs will first be briefly covered, followed by an introduction to their mechanisms of action and more detailed discussions of their discovery and the development of safe and efficient covalent enzyme inhibitors. All stages of a drug discovery program will be covered, from target considerations to lead optimization, strategies to tune reactivity and computational methods. The goal of this article is to provide an overview of the field and to outline good practices that are needed for the proper assessment and development of covalent inhibitors as well as a good understanding of the potential and limitations of current computational methods for the design of covalent drugs. [ABSTRACT FROM AUTHOR]