Fragment-based drug design (FBDD) has been widely adopted in both industry and academia and has proven to be a robust approach to identify small molecules that bind to a range of protein targets.1 Two compounds derived from programs of FBDD have now been approved for therapeutic use by the US Food and Drug Administration and many others are in advanced clinical trials.
One of the first practical implementations of FBDD was the approach of SAR-by-NMR described by Stephen Fesik’s group at Abbott,2 which employed protein-detected NMR experiments to identify ligands that bound at adjacent sites on a protein surface. Subsequently, both protein-detected and ligand-detected NMR experiments have been a mainstay of the screening approaches used in FBDD.
The value of NMR as a biophysical tool for screening fragment libraries is clear. However, the application of NMR extends beyond its role in screening. In this presentation I will highlight the use of NMR in the design and curation of fragment libraries, the optimization of conditions for screening as well as the identification of fragments that bind to a protein and a systematic approach to the prioritization of hits for further development.