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Acta Cryst. (2014). A70, C706
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Fragment-based approaches are now routinely applied for lead development in pharmaceutical drug research. Usually, a small but well selected library of low molecular weight compounds is pre-screened by biochemical or biophysical methods such as surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) or thermal shift assay; often followed for promising hit candidates by X-ray crystallography. We designed a small fragment library consisting of 364 compounds that is not strictly compliant to the otherwise often followed Astex rule of three for fragment library composition.[1] Thereafter, our library was validated on the pepsin-like aspartyl protease endothiapepsin, which serves as a model system for proteins that are involved in serious diseases such as malaria (plasmepsins), hypertension (renin) and Alzheimer's disease (ß-secretase) and therefore, is a valid target for further drug development. Due to the small size of fragments, they frequently exhibit only low affinity to the applied target protein and thus are often hard to detect in any screening approach, reflected in little overlap between different screening methods. After initial screening, we decided to validate the entire library by X-ray crystallography, which requires a steady supply of crystals, reproducible soaking conditions and a reliable setup at a synchrotron source, such as HZB BESSY II BL14.1 [2], preferably with some automation in initial data processing and refinement. A total hit rate greater than 10% was obtained, which will be compared to results from other screening methods. The resulting crystal structures will be discussed and provide an ideal basis for further lead development.

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Acta Cryst. (2014). A70, C711
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"Within the last decade, the fragment-based screening approach has been matured to a reliable and powerful instrument of pharmaceutical drug discovery. The success of fragment screening strongly depends on the quality of the chosen fragment library (100-200 Da), the quality of the target protein diffraction as well as the possibility to use high throughput methods for the screen application. A thorough crystallographic analysis of many protein-fragment complex structures and their binding modes has the perspective to result in the development of new potential lead structures and to map the interaction landscape of protein surfaces. Recently we started the development of a dedicated experimental facility for high throughput fragment screening at the BESSY II storage ring. The in house data processing pipeline ""XDSAPP"" [1] has been developed to speed up the data evaluation of large amounts of diffraction data. We have assembled a fragment library of 96 compounds and have validated this library against two target proteins. These first results suggest that our library is capable of identifying binding partners at a hit rate of close to 10%. This library together with a fully automated beam line [2] will be made accessible to users, thus enabling fragment-screening experiments on a much broader basis. "

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Acta Cryst. (2014). A70, C1681
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The Macromolecular Crystallography (MX) group at the Helmholtz-Zentrum Berlin (HZB) has been in operation since 2003. Since then, three state-of-the-art synchrotron beam lines (BL14.1-3) for MX have been built up on a 7T-wavelength shifter source [1,2]. Currently, the three beam lines represent the most productive MX-stations in Germany, with more than 1100 PDB depositions (Status 02/2014). BLs14.1 and 14.2 are energy tuneable in the range 5.5-15.5 keV, while beam line 14.3 is a fixed-energy side station operated at 13.8 keV. All three beam lines are equipped with state-of-the-art detectors: BL14.1 with a PILATUS 6M detector and BLs14.2 and 14.3 with large CCD-detectors. BL14.1 and BL14.2 are in regular user operation providing about 200 beam days per year and about 600 user shifts to approximately 70 research groups across Europe. BL14.3 has been equipped with a HC1 crystal dehydration device in 2011. In addition to serving the user community mainly as a screening and test beam line, it is currently the only MX beamline in Europe with a HC1 device permanently installed. Additional user facilities include office space adjacent to the beam lines, a sample preparation laboratory, a biology laboratory (safety level 1) and high-end computing resources. On the poster, a summary on the experimental possibilities of the beam lines and the ancillary equipment provided to the user community will be given.
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