Applications of NMR spectroscopy in FBDD

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Fragment-based drug design (FBDD) has become firmly established as a viable approach to the identification of starting points for the development of potent and selective compounds that modulate protein activity. As of 2017, the United States Food and Drug Administration have approved two molecules derived from FBDD for therapeutic use, many more are in advanced clinical trials, and the technology has been embraced by both academia and industry. The starting point for FBDD is the identification of very small molecules - "fragments" - that bind to a protein of interest. Due to their small size, fragments are able to sample chemical space more efficiently than larger molecules. This increases the likelihood of finding a "hit" - i.e., a fragment that binds to the desired protein. However, their small size also dictates that a fragment is likely to bind to its target protein with low affinity. For this reason, screening is generally carried out using biophysical binding assays rather than biochemical activity assays. Nuclear magnetic resonance (NMR) spectroscopy is an extremely powerful approach for detecting weak interactions. In fact the first implementation of FBDD employed NMR to characterize binding, andNMR remains a mainstay of many FBDD screening campaigns. NMR has a broader application in supporting programs of FBDD - it provides an essential component for quality control of the compounds in fragment screening libraries, it can be used to assess solubility, aggregation, and in addition to its role in screening to find fragment hits, it can be used to rank hits and assess their suitability for crystallographic structure determination in complex with a target protein. Where crystallography is not possible, several NMR-based approaches have been developed to determine structures of fragment-protein structures. In the current chapter we review these myriad applications of NMR in FBDD.

Original languageEnglish
Title of host publicationModern Magnetic Resonance
EditorsGraham A Webb
Place of PublicationCham Switzerland
Number of pages21
ISBN (Electronic)9783319283883, 9783319283890
ISBN (Print)9783319283876
Publication statusPublished - 13 Jun 2018


  • Compound aggregation
  • Fragment-based drug design
  • Library screening
  • Ligand observed NMR
  • Mixture design
  • Protein detection
  • Structure modeling
  • WaterLOGSY spectra

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