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Fragments from HEC-20

(1) The Frag Xtal Screen
(2) HEC-20 Slide Show

   



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   (1) The Frag Xtal Screen
   


In drug discovery, often small molecules ("fragments") are screened for efficient binding* to a specific protein target. Due to their small size, fragments can be chemically evolved or linked to each other, finally yielding a desired high-affinity lead structure[1] (Fig. 1).


Figure 1: Fragment-based lead discovery takes advantage of fragment evolution and linking. Small individual fragments with inherently low affinity but high efficiency* are grown according to the structural model. The efficient binding of the fragments results in a nanomolar lead structure[1].


The new Frag Xtal Screen is based on the approach "Crystallography first": X-ray crystallography shows not only whether a fragment binds to the protein but also where and how the binding occurs. Crystals of the target protein are soaked with distinct fragments and their structural data are directly collected.

Our new Frag Xtal Screen...

  • ...consists of 96 fragments covering a large chemical space, selected by the groups of Gerhard Klebe (University of Marburg) and Manfred Weiss (BESSY II) based on
    • a priori validation through compound selection from PDBeChem entries[5]
    • proven capability of fragments to bind to proteins[2,5]
    • validation with aspartic protease endothiapepsin (EP), hit rate 10 %[2]
  • ...allows crystal soaking with fragment concentrations > 90 mM resulting in functional mapping of the entire target and identification of multiple binding sites
  • ...avoids losing potential hits that are not identified by prescreening methods[3,4]

Assuming practical skills in transferring crystals and cryocooling, 96 distinct fragments can be screened within one week.

Not sure if fragment screening is a suitable approach for your project?
Contact us at xtals@jenabioscience.com!


References:
[1] Rees et al. (2004) Fragment-based lead discovery Nat. Rev. Drug Discov. 3:660.
[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] www.ebi.ac.uk/pdbe-srv/pdbechem

* binding efficiency = high binding energy/molecular mass


   
   (2) HEC-20 Slide Show
   


Thanks to the organizers from Matthias Bochtler's group! It was a great pleasure to attend the conference and the social events!

Check out the pictures in our gallery!

   
   
   
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