Solution NMR spectroscopy plays important roles in understanding protein structures,
dynamics and protein-protein/ligand interactions. In a target-based drug discovery project,
NMR can serve an important function in hit identification and lead optimization. Fluorine
is a valuable probe for evaluating protein conformational changes and protein-ligand interactions.
Accumulated studies demonstrate that 19F-NMR can play important roles in fragment-
based drug discovery (FBDD) and probing protein-ligand interactions. This review
summarizes the application of 19F-NMR in understanding protein-ligand interactions and drug
discovery. Several examples are included to show the roles of 19F-NMR in confirming identified
hits/leads in the drug discovery process. In addition to identifying hits from fluorinecontaining
compound libraries, 19F-NMR will play an important role in drug discovery by
providing a fast and robust way in novel hit identification. This technique can be used for
ranking compounds with different binding affinities and is particularly useful for screening
competitive compounds when a reference ligand is available.
Keywords: 19F NMR, drug discovery, protein structure, hit to lead, hit identification, protein-ligand interactions.
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