We apply fragment-based drug discovery on disease-relevant proteins in order to identify novel chemical probes and therapeutic principles
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).
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 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 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.
We thank the following foundations for their generous support of our research:
• HALOS Cross Border Research Grant (2019)
• Augustinus Foundation (2014, 2016, and 2018)
• China Scholarship Council (2017, 2018, and 2019)
• DRA/Lundbeck Foundation scholarship (2017)
• Lundbeck Foundation - Fellowship Starting Grant (2015) and Travel Grants (2017)
• The A.P. Møller Foundation for the Advancement of Medical Science (2014)
• Weimann Grant (2014)
• Hørslev Foundation (2014)
If you are you interested in doing a master thesis project in the group, please send your CV, grades and motivations to firstname.lastname@example.org for further discussions. We have projects both within chemistry and biological areas of drug discovery.
- See examples of Master Thesis Projects here.
Currently we have no open PhD and postdoc positions in our group, but we are always interested in hearing from talented and potential candidates. If you are interested in becoming part of our group please send your CV and motivations to email@example.com.
Sara Marie Øie Solbak (March 2016 – March 2019)
Jakob Staun Pallesen (Jan 2016 – June 2019)
Giuseppe Marseglia (exchange from Parma University) (Nov 2018 – April 2019)
Lars Jakobsen Høj (Sept – Dec 2017)
Dorleta Gonzalez Chichon (Sept 2018 – Aug 2019)
Erik Bjørn Dampe (Sept 2018 – Aug 2019)
Martina Luchini (Erasmus) (March – Aug 2019)
Kim Tai Tran (incl. Scholar project) (Sept 2017 – April 2019)
Nanna Haapanen (Sept 2017 – Jan 2019)
Rosa Macarena Carrasquilla Carmona (Sept 2016 – Aug 2017)
Lars Jakobsen Høj (Feb – Aug 2017)
Anthony Garcia (Erasmus) (Feb – Aug 2017)
Federico Munafo (Erasmus) (Oct 2016 – March 2017)
Alejandro Escobar Peso (Erasmus) (Oct 2016 – Jan 2017)
Alejandro Aguayo Orozco (Sept 2014 – Aug 2015)
Thomas Breum Pedersen (Sept 2014 – Aug 2015)
Kim Tai Tran (Jan - June 2016)