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


Recomendação de Literatura sobre Fragment Screen

[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.

Citações Recentes do 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.