Fragment-based drug discovery campaigns guided by native mass spectrometry

Native mass spectrometry (nMS) is well established as a biophysical technique for characterising biomolecules and their interactions with endogenous or investigational small molecule ligands. The high sensitivity mass measurements make nMS particularly well suited for applications in fragment-based drug discovery (FBDD) screening campaigns where the detection of weakly binding ligands to a target biomolecule is crucial. We first reviewed the contributions of nMS to guiding FBDD hit identification in 2013, providing a comprehensive perspective on the early adoption of nMS for fragment screening. Here we update this initial progress with a focus on contributions of nMS that have guided FBDD for the period 2014 until end of 2023. We highlight the development of nMS adoption in FBDD in the context of other biophysical fragment screening techniques. We also discuss the roadmap for increased adoption of nMS for fragment screening beyond soluble proteins, including for guiding the discovery of fragments supporting advances in PROTAC discovery, RNA-binding small molecules and covalent therapeutic drug discovery.