Covalent inhibitors design and discovery

Abstract

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.

Keywords: Binding kinetics; Covalent drugs; Docking; Drug design.