Proteome-Wide Fragment-Based Ligand and Target Discovery

Chemical probes are invaluable tools to investigate biological processes and can serve as lead molecules for the development of new therapies. However, despite their utility, only a fraction of human proteins have selective chemical probes, and more generally, our knowledge of the chemically-tractable proteome is limited, leaving many potential therapeutic targets unexploited. To help address these challenges, powerful chemical proteomic approaches have recently been developed to globally survey the ability of proteins to bind small molecules (i. e., ligandability) directly in native systems. In this review, we discuss the utility of such approaches, with a focus on the integration of chemoproteomic methods with fragment-based ligand discovery (FBLD), to facilitate the broad mapping of the ligandable proteome while also providing starting points for progression into lead chemical probes.

Automated summary

Chemical probes are important tools for studying biological processes and developing therapies, but only a small fraction of human proteins have selective chemical probes. Our understanding of the chemically-tractable proteome is limited, resulting in many unexploited therapeutic targets. To address these challenges, powerful chemical proteomic approaches have been developed to globally survey protein-ligand interactions in native systems. This review discusses the utility of these approaches, particularly in conjunction with fragment-based ligand discovery (FBLD), to map the ligandable proteome and identify lead chemical probes.