Fluorine Fragment Cocktails

Fragment-based drug discovery (FBDD) projects performed with 19F NMR-assisted screening are becoming an essential and widespread method in drug discovery. Fluorine yields a strong, sharp and distinct signal in NMR spectra. It has a wide chemical shift range and is highly sensitive to the immediate molecular environment. These factors allow an efficient application of this method in laboratories with limited NMR setup and screening several compounds together without them interfering with each other.

Additionally, the efficacy of fragment screening can be increased substantially by pooling or cocktailing the compounds in the library. Identification of the bound fragment at the end of the NMR experiments then becomes a case of determining the best fragment-fit.

Life Chemicals has designed its unique Fluorine Fragment Cocktail Library employing several physicochemical parameters and medicinal chemistry structure filters. The choice of fluorinated fragments present in the library is fundamental to ensure broad coverage of chemical space and the local environment of fluorine.

The Library is pooled in sets of 10 fragments with the most different 19F chemical shifts in order to facilitate screening results interpretation. Carefully collected 135 Fluorine Fragment Cocktails comprises 1,350 in-stock drug-like fluorine-containing fragments that satisfy the following parameters:

  • Single-type fluorine group
  • Only 1 peak in the 19F NMR spectrum in the majority of cases
  • Purity > 90 %
  • DMSO soluble at 200 mM

Overall physicochemical parameters of the Library:

  • 85 < MW < 300
  • -2.0 < ClogP < 4.6
  • H-bond Donors ≤ 4
  • H-bond Acceptors ≤ 6
  • Rotatable bonds ≤ 10
  • TPSA ≤ 120 Å2

An example of the 19F NMR spectrum of the fragment cocktail 1 with signals attributed to each compound is depicted in Figure 1. 

Figure 1. 19F NMR spectrum of the fragment cocktail 1. All peaks are assigned to the corresponding fluorine-containing fragments.

References

  1. Nagatoishi S, Yamaguchi S et al. Bioorg Med Chem. 2018 May 1; 26(8):1929-1938.
  2. Norton, R.; Leung, E.; Chandrashekaran, I.; MacRaild, C. Molecules 2016, 21 (7), 860.
  3. Nosik, P. S., Gerasov, A. O. et al. Adv. Synth. Catal. 359 (2017), 3126-3136
  4. Gerasov, A., Dolgonos, G. A. et al. Synthesis (Stuttg). Published online: 2020 Jan.
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