Bach Group

We apply fragment-based drug discovery on disease-relevant proteins in order to identify novel chemical probes and therapeutic principles

Biological active small-molecule

In our group we develop biological active small-molecule inhibitors against key CNS proteins involved in excitotoxicity and oxidative stress. We evaluate the druggability of selected targets and aim at developing new high-quality chemical probes useful for pharmacological studies and for identifying new therapeutic principles against ischemic stroke and related diseases.

Fragment-based drug discovery (FBDD) is a core theme of our research. We screen our library of >2500 fragments (small substructures of drug like molecules) using biochemical and sensitive biophysical methods, such as SPR and ligand-based NMR. Promising hits are optimized into lead molecules by medicinal chemistry, biostructural studies (2D NMR and X-ray crystallography), and pharmacology.

Biochemical assays, SPR*, and medicinal chemistry comprise core competencies within the group, and X-ray crystallography is performed in close collaboration with internal colleague Prof. Michael Gajhede using various beamlines in Europe, including ESRF (Grenoble), EMBL (Hamburg), MAX IV (Lund), and Diamond Light Source (Oxfordshire). NMR for studying ligand-protein interactions is conducted with collaborators in Germany (Helmholtz Zentrum München) and Denmark (Technical University of Denmark), and testing in disease models by collaborators in Denmark (University of Copenhagen and University of Southern Denmark).
(*See SelectScience interview  about our Pioneer system and how we use it)

Another theme of our research is to develop multi-target inhibitors, which are likely to provide greater effects against complex diseases, such as ischemic stroke. We hope that FBDD can be used as a tool to directly search for multi-target hits, which can then be optimized into larger and more efficient multi-target inhibitors.

We are also engaged in collaborative projects within brain cancer (with Asc. Prof. Petra Hamerlik, Danish Cancer Society Research Center) and bacterial targets (with Prof. Morten O. A. Sommer, Technical University of Denmark).

Research Projects

keap1

Keap1’s Kelch-DC domain interacts with Nrf2. Inhibition of this protein-protein interaction leads to Nrf2 nucleus translocation and transcription of antioxidant genes and thus cellular protection.

NADPH

NADPH oxidase is a superoxide-producing membrane-bound enzyme complex. Compounds targeting the SH3 domains of p47 can prevent assembling of the complex and lead to less toxicity.

PSD-95

PSD-95 binds the NMDA receptor and nNOS. Compounds targeting PDZ1-2 of PSD-95 disrupt this ternary protein complex and lead to less excitotoxicity-mediated nitric oxide and thus cell protection.