Easy entry to fragment-based lead discovery (FBLD) by crystallographic screening:
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
For in vitro use only!
Shipping: shipped at ambient temperature
Storage Conditions: store in aluminum bag at -20 °C
Shelf Life: 12 months
Description:
The Frag Xtal Screen provides 96 different fragments. Two protein wells are spotted with 50 nmol fragment each while the third one is kept free. This allows to vary the stabilizing solution, e.g. the DMSO content.
Crystallographic screening and the structural data collected are the only reliable information to verify fragment binding for structure-based drug design. It was shown that the biochemical and biophysical assays routinely performed as prescreens show distinct hits with minimal overlap eliminating promising candidates and maybe focussing on the poor ones [1-3]. The Frag Xtal Screen is designed to directly collect structural data of protein crystals soaked with 96 different fragments.
Applications:
Fragment-based lead discovery (FBLD) by crystallographic screening
Protein surface mapping by crystallographic screening
Short Fragment Soaking Protocol:
1) Remove foil carefully
2) Add 30 μl crystallization buffer to the reservoir (manually or by robot)
3) Add 0.5 μl crystallization buffer on dried fragments (manually or by robot)
4) Add 1-2 crystals per drop
5) Seal the plate & incubate 1-48 h
6) Fish & cryo-cool at least one crystal per condition
The fragment screen was developed by Jena Bioscience in cooperation with the HZB MX-groupat BESSY II (AG Weiss) and the Institute of Pharmaceutical Chemistry, University of Marburg (AG Klebe).
Fragment Screening Poster
MSDS
Datasheet
Screen Formulation
For any questions about the JBS Frag Xtal Screen please call +1 607 266 8877 or email support@mitegen.com.
[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.
