10 September 2012

Fluorine Fetish

As readers of this blog may know, I love 19F NMR. 19F NMR is well known in screening applications, like FAXS (fluorine chemical shift anisotropy and exchange for screening) and FABS (fluorine atoms for biochemical screening). Back in January, I reviewed a very nice paper from Amgen on the subject. Now, Anna Vulpetti and Claudio Dalvit, the father of 19F in industry, have a review out in Drug Discovery Today on Post Screen applications. This review tries to make the case for ubiquitous use of 19F.
They propose a complete workflow for using 19F NMR (Figure Above). They point out the variety of ways that fluorine can impact the H2L stage. Flourine has many advantages when replacing proton: increased metabolic stability, increased acidity, and decreased basicity. Lipophilicity is increased if the fluorine is near a basic nitrogen or on a aromatic ring. Permeability can be increased. Fluorine can also be a powerful binding moiety by means of H-bond interactions, lipophilic contacts and multipolar and/or antiparallel polar interactions, indirect contact with the protein mediated by water molecules, or by preorganizing the ligand conformation as needed for the protein recognition.

However, this leads to a point Dan made almost three years ago:
I wondered why fluorine-labeled fragments are not used more widely; 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?
To my eyes, I would think the following (far from an exhaustive list) could each or together be reasons why 19F hasn't received wider uptake:
  1. Not everyone has 19F probe they can dedicate to screening, follow up, etc.
  2. 19F libraries require a lot of work to put together
  3. 19F is magic methyl by another name
  4. See 1.

Let us know your thoughts in the comments.


Morten Grøftehauge said...

That figure is really blurry.
Feel free to delete this comment.

Anonymous said...

I will do this more if you buy me a 19F cryoprobe ...