Covalent fragment libraries in drug discovery

Abstract

Targeted covalent inhibitors and chemical probes have become integral parts of drug discovery approaches. Given the advantages of fragment-based drug discovery, screening electrophilic fragments emerged as a promising alternative to discover and validate novel targets and to generate viable chemical starting points even for targets that are barely tractable. In this review, we present recent principles and considerations in the design of electrophilic fragment libraries from the selection of the appropriate covalent warhead through the design of the covalent fragment to the compilation of the library. We then summarize recent screening methodologies of covalent fragments against surrogate models, proteins, and the whole proteome, or living cells. Finally, we highlight recent drug discovery applications of covalent fragment libraries.