New substance library to accelerate the search for active compounds
For the study, the enzyme endothiapepsin (grey) was combined with molecules from the fragment library. The analysis shows that numerous substances are able to dock to the enzyme (blue and orange molecules). Every substance found is a potential starting point for the development of larger molecules. © J. Wollenhaupt/HZB
The fragment libraries, which the MX team has assembled together with a group from the University of Marburg, are also available to users at BESSY II. The diagram shows the fragment-screening workflow. © HZB
In order to accelerate the systematic development of drugs, the MX team at the Helmholtz-Zentrum Berlin (HZB) and the Drug Design Group at the University of Marburg have established a new substance library. It consists of 1103 organic molecules that could be used as building blocks for new drugs. The MX team has now validated this library in collaboration with the FragMAX group at MAX IV. The substance library of the HZB is available for research worldwide and also plays a role in the search for substances active against SARS-CoV-2.
For drugs to be effective, they usually have to dock to proteins in the organism. Like a key in a lock, part of the drug molecule must fit into recesses or cavities of the target protein. For several years now, the team of the Macromolecular Crystallography Department (MX) at HZB headed by Dr. Manfred Weiss together with the Drug Design Group headed by Prof. Gerhard Klebe (University of Marburg) has therefore been working on building up what are known as fragment libraries. These consist of small organic molecules (fragments) with which the functionally important cavities on the surface of proteins can be probed and mapped. Protein crystals are saturated with the fragments and then analysed using powerful X-ray light. This allows three-dimensional structural information to be obtained at levels of atomic resolution. Among other things, it is possible to find out how well a specific molecule fragment docks to the target protein. The development of these substance libraries took place as part of the joint Frag4Lead research project and was funded by the German Federal Ministry of Education and Research (BMBF).
The MX team (MX stands for Macromolecular Crystallography) has now published the design of a chemically diverse fragment library called the “F2X-Universal“ library, which consists of 1,103 compounds. A representative selection of 96 compounds has been extracted from this library, which is referred to as the F2X Entry Screen. In the course of publishing the library, this selection has now been successfully tested and validated by the MX team of the HZB at the MAX IV X-ray source in Lund, Sweden and at BESSY II.
In the study, the HZB and MAX IV teams verified the efficiency of the F2X Entry library by screening endothiapepsin and the Aar2/RnaseH protein complex as the target enzymes. In the next step, the MX team will use the entire universal library.
“For the current study, the fragment screening experts at HZB - BESSY II worked very closely with the FragMAX project team at MAX IV“, said Dr. Uwe Müller from the MX team at HZB who helped to set up the three MX beamlines at BESSY II as well as the BioMAX beamline at MAX IV. “This enabled both partners to further develop their own technology platforms and use them for imaging the functional surfaces of different proteins. This will be an excellent basis for future collaboration between MAX IV and HZB.“
- Green Deal Ukraina: HZB launches an Energy & Climate ProjectGreen Deal Ukraina, funded by the German Federal Ministry of Education and Research, is working with partner institutions in Ukraine and Poland to establish an energy and climate think tank in the capital, Kiev. The aim is to provide independent and evidence-based advice on rebuilding a sustainable energy system in Ukraine. After all, the implementation of energy and climate legislation is a prerequisite for Ukraine's accession to the EU. The project started on 1 June 2023 and will run for four years.
- Spintronics at BESSY II: Domain walls in magnetic nanowiresMagnetic domains walls are known to be a source of electrical resistance due to the difficulty for transport electron spins to follow their magnetic texture. This phenomenon holds potential for utilization in spintronic devices, where the electrical resistance can vary based on the presence or absence of a domain wall. A particularly intriguing class of materials are half metals such as La2/3Sr1/3MnO3 (LSMO) which present full spin polarization, allowing their exploitation in spintronic devices. Still the resistance of a single domain wall in half metals remained unknown. Now a team from Spain, France and Germany has generated a single domain wall on a LSMO nanowire and measured resistance changes 20 times larger than for a normal ferromagnet such as Cobalt.
- Fractons as information storage: Not yet quite tangible, but closeA new quasiparticle with interesting properties has appeared in solid-state physics - but so far only in the theoretical modelling of solids with certain magnetic properties. An international team from HZB and Freie Universität Berlin has now shown that, contrary to expectations, quantum fluctuations do not make the quasiparticle appear more clearly, but rather blur its signature.