Fragment-based lead discovery owes much of its popularity to NMR: the SAR by NMR papers published by Abbott in the mid 1990s demonstrated both the power and the practicality of the approach. Recently SPR has also come into its own as a means for screening fragments, and in a paper in this month’s issue of Drug Discovery Today Claudio Dalvit of Novartis and the Italian Institute of Technology compares these two techniques, along with fluorescence spectroscopy. Not surprisingly given the author’s longstanding research interest, NMR comes out favorably, though with the recommendation that the techniques are complementary, so researchers should combine techniques rather than simply selecting one over another.
As I read the paper, I wondered why fluorine-labeled fragments are not used more widely; Dalvit’s group published another paper about this approach recently in JACS. Fluorine has a strong NMR signal and is very sensitive to the local environment, so when a fluorine-containing fragment binds to a protein this can be easily detected. In fact, the dynamic range for this type of assay is so great that fragment binding can be detected at concentrations several orders of magnitude lower than their dissociation binding constants.
This seems like a very powerful approach, but I haven’t seen many other people using it. Are folks concerned about the need for fluorine in every fragment (although many are commercially available) or is there something else I’m missing?