NMR vs other methods

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?

Genentech’s affinity for Graffinity

Heidelberg-based Graffinity today announced that they would be collaborating with the Genentech division of Roche. Graffinity will apply its surface plasmon resonance (SPR) fragment-based technology to several Genentech targets. Financial details and specific targets have not been released, though Graffinity CEO Kristina Schmidt is quoted as saying that they plan “to explore drug targets that would remain white spaces on the map of drug discovery” with conventional high-throughput screening.

SPR is rapidly becoming a workhorse in the stable of FBDD techniques. Although it provides less information than NMR or X-ray approaches, SPR is faster, and can rapidly distinguish true hits from bad-acting artifacts. Typically a protein is immobilized on a gold surface, and fragments are allowed to flow past to detect those that bind. Graffinity reverses this process: they have a collection of about 110,000 small molecules, just over a fifth of which are fragments, immobilized in microarrays which can be screened against proteins (see here for full description).

Genentech is no stranger to SPR; one of the highlights of the recent FBLD 2009 meeting was a talk by Tony Giannetti on the use of this technology at Genentech against roughly 40 target proteins. The collaboration further validates the use of SPR for FBDD, and suggests that Graffinity has an interesting – and useful – angle.