Advancing Target Validation and Ligandability Assessment: Fragment Screening via ¹⁹F NMR Spectroscopy

In drug discovery, precise target validation and ligandability assessment are pivotal processes. This article introduces an advanced protocol employing fluorine-19 (¹⁹F) NMR spectroscopy for fragment-based screening (FBS). This innovative methodology distinguishes fragment hits and elucidates their binding interactions, even within millimolar concentration ranges. Leveraging the distinctive advantages of ¹⁹F NMR, such as high signal dispersion, background-free spectra, and heightened sensitivity to protein binding, this technique emerges as a potent tool for early-stage drug discovery. The demonstrated application of this protocol in target validation, with a specific emphasis on ligandability assessment, provides a means to gauge the inherent challenges associated with a target right from the outset of a project.