image: User interface for FragMAX screening platform at MAX IV
Researchers at Helmholtz-Zentrum Berlin (HZB), in collaboration with MAX IV’s BioMAX team, have validated a new diverse universal compound library used in the process of drug discovery and development. The HZB study, published in CellPress, sourced the power of MAX IV’s macromolecular crystallography beamline BioMAX and its screening platform FragMAX for fast, efficient measurement of the 3D crystalline structure of selected test enzymes. Further, the library study is a first user application for FragMAX’s novel analysis software.
“This was a first test of the software, and the first output of FragMAX as a user facility,” said Gustavo Lima, FragMAX project manager and scientist at BioMAX beamline. “It’s now that the platform has a user case [delivered] for publication.” Lima developed the FragMAX software when initially joining MAX IV in 2018.
Crystallographic fragment screening (CFS) is a method which allows one to explore new compounds or molecular combinations, and functionalities possible to exploit—thus offering researchers potential leads to new study pathways. Access to a diverse library composed of fragments or small organic molecules, is essential for CFS work and extremely valuable for pharmaceutical development.
The new HZB fragment collections, namely the F2X-Universal library consisting of 1103 fragments, and the F2X-Entry library containing a sub-selection of 96 members, offer users a heterogeneous span of compounds for screening the surface of proteins and their potential interactions. Like puzzle pieces that fit together, a specific fragment matches a protein if the combination produces a desired interaction or change in a molecule.
In the study, researchers verified the efficiency of the F2X-Entry library by screening target enzymes Endothiapepsin and the Aar2/RNaseH complex, which returned high hit rates and varied binding sites. The X-ray data collection and data analysis for the screening were carried out at MAX IV laboratory. Verification of the F2X-Universal library has already been performed at BioMAX.
“The published study demonstrates a very successful international collaboration between the Berlin fragment screening experts from HZB – BESSY II and the FragMAX project team of MAX IV,” said Uwe Müller, study collaborator and beamline scientist for macromolecular crystallography at Helmholtz-Zentrum Berlin. “Within this work, both partners were able to advance their own technology platforms and apply those to map the functional surfaces of various proteins. This is a great basis for future collaborations between MAX IV and HZB.”
Use of the fragment screening platform FragMAX is a straightforward process. Crystalline samples can be brought or produced in-house at Lund Protein Production Platform at Lund University, a partner facility of MAX IV for protein-related experiments. Users have access to fragment library FragMAXlib for screening samples. Data collection is done at X-ray macromolecular crystallography beamline BioMAX, and in the future, with MicroMAX beamline. In a final step, users can analyse data systematically with MAX IV software.
“The software reads all the experiments from the beamline. It offers users analysis tools and returns all results from these. Instead of taking weeks or months, the process only takes a few days to do everything,” said Lima.
According to the global standard Protein Data Bank (PDB), MAX IV’s BioMAX beamline is among the most productive in the world for output of protein crystallography data in 2020.
Wollenhaupt et al., 2020, F2X-Universal and F2X-Entry: Structurally Diverse Compound Libraries for Crystallographic Fragment Screening. Structure 28, 694–706 June 2, 2020 ©2020 Elsevier Ltd. https://doi.org/10.1016/j.str.2020.04.019