09 December 2019

A new library of fluorinated Fsp3-rich fragments

Among fragment-finding methods, ligand-based NMR ranks near the top in terms of popularity. Of its many variations, fluorine (19F) NMR appears to be gaining in popularity. Fluorine NMR has several advantages, including high sensitivity and the fact that many fragments can be screened simultaneously because of the wide chemical shift range for fluorine. Although more commercial fluorine-enriched libraries are available now than when we first wrote about the approach a decade ago, the diversity of these libraries is still somewhat limited. This problem has been tackled by Mads Clausen at the Technical University of Denmark and an international team of collaborators in a new Angew. Chem. Int. Ed. paper.

The researchers wanted to create a fluorinated fragment library that would be not just diverse but also contain a high fraction of sp3-hybridized carbons (high Fsp3). Some of the early claims around “three dimensional” fragments have been questioned, and there seems to be little if any correlation between the shapeliness of fragments and that of derived leads, but if you’re going to make new fragments in academia it makes sense to explore interesting molecular architectures.

Starting from just six simple building blocks, each containing a trifluoromethyl group, the researchers generated nine different cores which were further derivatized at multiple positions to yield 115 diverse fragments. Consistent with diversity-oriented synthesis, no more than five synthetic steps were used for any molecule. All molecules were made as racemates in order to further increase the diversity of the library.

The resulting “3F Library” is mostly rule-of-three compliant, though given that the trifluoromethyl moiety alone adds 69 Da the fragments do tend to be larger, with an average molecular weight of 284 Da. They are, however, less lipophilic than two commercial fluorinated fragment libraries. And with an average Fsp3 = 0.7 and 3.3 chiral centers they are also quite shapely as assessed by principal moment of inertia.

Building a library is nice, but will it provide hits? To find out, the researchers screened the 102 fragments that passed quality control against four targets. They used a transverse (T2) relaxation assay (specifically, CPMG) in which fragments bound to a protein tumble more slowly, causing a reduction in 19F signal intensity. Hit rates ranged from 3% to 11%, and about two thirds of these confirmed in STD or WaterLOGSY assays. As seen by the examples shown here, the fragments are quite diverse.

Whether these hits will lead to more potent molecules remains to be seen. Laudably the paper ends with the statement: “we hope that the 3F library will find use for other researchers and we encourage anyone interested in screening the fragments to contact us.” If you are looking for interesting new fragments that are tailored for follow-up chemistry, I encourage you to take the team up on their offer.


Mads H. Clausen. said...

Dear Dan
Thank you for highlighting our 3F Library and for the nice comments. We agree completely that it will be interesting to see if these starting points will lead to better ligands in the years to come. For now we were encouraged to see that different scaffolds came up as hits for the four proteins we screened.

Peter Kenny said...

Hi Dan, although I criticized the study in which Fsp3 was introduced, I agree that getting more saturated carbon atoms into fragments is a good design theme. I would argue that the rationale for doing so is based more on molecular diversity than the idea that Fsp3-rich fragments are inherently better compounds than Fsp3-poor fragments. In the correlation inflation article that you’ve referred to, we actually suggested biasing substituents towards axial positions, with minimal steric footprint, as a molecular design theme. My view of the featured library is that many of the fragments appear to be of relatively high molecular complexity and this is likely to compromise their ability to cover chemical space in an optimal manner.