Fragment-based drug discovery is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Here we present the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp3-rich fragments is shape diverse and natural product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of 19F- followed by 1H-NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67% validation rate was achieved using secondary assays. This is the first synthetic fragment library tailor-made for 19F-NMR screening and our results underline that the approach should find broad application in the FBDD community.
- Fragment-based drug discovery
- Molecular diversity
- NMR spectroscopy
- Synthesis design