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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[5].
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

BIOZ Product Citations

Please click the arrow on the right to expand the citation list. Click publication title for the full text.

Further Literature Citations of Frag Xtal Screen

  • Lima et al. (2021) FragMAXapp: crystallographic fragment-screening data-analysis and project-management system. Acta Cryst. D 77:799.
  • Švecová et al. (2021) Crystallographic fragment screening-based study of a novel FAD-dependent oxidoreductase from Chaetomium thermophilum. Acta Cryst. D 77:755.
  • Opassi et al. (2020) Establishing Trypanosoma cruzi farnesyl pyrophosphate synthase as a viable target for biosensor driven fragment-based lead discovery. Protein Science 29:977.
  • Lima et al. (2020) FragMAX: the fragment-screening platform at the MAX IV Laboratory. Acta Cryst. D 76:771.

References and Recommended Literature

[1] Wollenhaupt et al. (2021) Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin. J. Vis. Exp. 169:e62208.
[2] 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.
[3] 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.
[4] Schiebel et al. (2015) One Question, Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists. ChemMedChem 10:1511.
[5] Hajduk and Greer (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews Drug Discovery 6:211.
[6] Rees et al. (2004) Fragment-based lead discovery. Nature Reviews Drug Discovery 3:660.