Jena Bioscience GmbH

Löbstedter Str. 71

07749 Jena, Germany

Tel.: +49-3641-628-5000

Fax: +49-3641-628-5100

Web: www.jenabioscience.com

Christin Reuter

Wojanów Palace, September 28 th 2017

Fragment ScreeningThe *Frag Xtal Screen* for

crystallographers

Cover a large chemical space by screening fragments

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Fragments Compounds

Molecular Weight 100-250 Da 300-500 Da

Binding Affinity Low High

“Six biophysical screening methods miss a large pro portion of crystallographically discovered fragment hits” [1]

Fragment Screening

[1] 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.

Several methods for fragment screening available: X-ray crystallography is one of them

Fragment screening by X-ray crystallographygives direct answers

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[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.

Crystallographic fragment screening is now a straig htforward & user-friendly experiment

Figure adapted from Rees et al. (2004) Fragment-Based Lead Discovery Nat. Rev. Drug Discov. 3:660.

• Can cover hits not identified by other methods [1-3]

• Identifies several binding sites on the target (protein)

• Yields binding information at atomic level

• Allows structure-guided fragment evolution towardshigh (nM) affinity binders

For an easy start: The Frag Xtal Screen as 96 well pla te(Initial idea developed at a previous HEC meeting)

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EP Active Site

EP Remote

PKA Kinase

PIM Kinase

Carbonic Anhydrase

Thrombin

17βHSD14

TGT

Thermolysin

7+ Other Targets

PDB

96 fragments produced 145 in-house hits + 8 pdb hits (light blue)

figure used by courtesy of Dr. Alexander Metz, University of Marburg

Frag Xtal Screen: A validated library (chemically di verse, highly soluble) for improved hit rates

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96 dried fragments(2 x 50 nmol each)

are provided in a crystallization

plate

Fragment Screening Plate from Jena Bioscience

Crystal soaking

Cryocooling

Automated datacollection

Fragment solubilizationin crystallization buffer

Affordable for any Xtals lab …

Thank you !

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HZB MX-group at BESSY II

Manfred Weiss

Franziska Huschmann

Institute of Pharmaceutical Chemistry, University of Marburg

Gerhard Klebe

Alexander Metz

Contact us at xtals@jenabioscience.com