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Screening - Fragment Screen

A major challenge in drug discovery is the identification of chemical moieties that specifically interact with a particular protein target. Traditionally, this was addressed by High Throughput Screening (HTS) however, recently “Fragment Screening” has become increasingly popular. In a Fragment Screen a set of small molecules (“fragments”), typically with MW < 300 Da and with low affinities, are evaluated for specific interaction with the target. Crystallography/X-ray diffraction shows not only whether a fragment binds to the protein but also where and how the binding occurs and is therefore the favored screening method. Hit-fragments are subsequently chemically modified in several optimization/screening cycles until a high affinity lead structure is obtained. Since such a fragmented approach allows screening of broader chemical space compared to large, distinct libraries, the hit rates of Fragment Screens are believed to be 10-1000x higher than those in traditional HTS[4].
The Frag Xtal Screen offers an easy entry to fragment-based lead discovery (FBLD) by crystallographic screening:

  • 96 fragments
  • High fragment solubility allows high soaking concentrations (> 90 mM; may depend on soaking conditions)
  • In-house tests with high crystallographic hit rates
  • Validated X-Ray hits for diverse target classes in the PDB
  • Diverse and representative fragment library for large chemical space
  • Straight-forward follow-up compounds available

References / Recommended Literature

[1] Huschmann et al. (2016) Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library. Acta Cryst F 72:346.
[2] Schiebel et al. (2016) Six Biophysical Screening Methods Miss a Large Proportion of Crystallographic Discovered Fragment Hits: A Case Study. ACS Chem. Biol. 11:1693.
[3] Schiebel et al. (2015) One Question, Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists. ChemMedChem 10:1511.
[4] Hajduk and Greer (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews Drug Discovery 6:211.
[5] Rees et al. (2004) Fragment-based lead discovery. Nature Reviews Drug Discovery 3:660.