Employees – University of Copenhagen

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Department of Drug Design and Pharmacology > Employees

Lars Olsen

Lars Olsen

Associate Professor

Our research focus areas have been on the rationalizing the recognition between biological molecules. This concerns the binding of small ligands or peptides to proteins and the chemical process done by enzymes. The focus has been on Cytochrome P450 enzymes, Histone Demethylases, Glutamate Receptors, and Peptide Transporters.

In the research, computational chemistry techniques like density functional theory, molecular dynamics, and QM/MM are applied. In addition, experimental binding assays are used to test the hypothesis generated with the theoretical methods. 

One of the major achievements concerns how a particular class of enzymes, the cytochrome P450 enzymes, recognize and react with their substrates. For that purpose we have developed a tool for prediction of metabolism (www.farma.ku.dk/smartcyp) that researchers in academia and industry.

Another strong focus area is to rationalize the thermodynamics upon molecular recognition using methods in computational chemistry. To complement computational chemistry-based investigations, we use isothermal titration calorimetry to measure binding affinities (Gibbs free energies), enthalpies and entropies. These measurements have successfully been applied in a number of projects, in particular the glutamate receptor system. 

We have contributed to the research on histone demethylases. Our goals are to understand the function of these enzymes and use that knowledge to design high affinity compounds to be used in treatment in cancer and inflammatory diseases. The current status is that the production of proteins and bioassays has been established and the first inhibitors identified (small molecule compounds and peptides).

Selected references on Cytochrome P450 enzymes:

Olsen, L., Rydberg, P., Rod, T. H. & Ryde, U. (2006) Prediction of activation energies for hydrogen abstraction by cytochrome p450, J Med Chem. 49, 6489-6499.
Rydberg, P., Gloriam, D. E. I., Zaretzki, J., Breneman, C. & Olsen, L. (2010) SMARTCyp: A 2D method for prediction of cytochrome P450-mediated drug metabolism, ACS Med Chem Lett. 1, 96-100.
Rydberg, P., Jørgensen, M. S., Jacobsen, T. A., Jacobsen, A.-M., Madsen, K. G. & Olsen, L. (2013) Nitrogen Inversion Barriers Affect the N-Oxidation of Tertiary Alkylamines by Cytochromes P450, Angew Chem Int Ed. 52, 993-997.
Rydberg, P., Jørgensen, F. S. & Olsen, L. (2014) Use of density functional theory in drug metabolism studies, Expert Opinion on Drug Metabolism & Toxicology. 10, 215-227.

Selected references on Receptors:

Naur, P., Hansen, K. B., Kristensen, A. S., Dravid, S. M., Pickering, D. S., Olsen, L., Vestergaard, B., Egebjerg, J., Gajhede, M., Traynelis, S. F. & Kastrup, J. S. J. (2007) Ionotropic glutamate-like receptor d2 binds D-serine and glycine, Proceedings of the National Academy of Sciences of the United States of America. 104, 14116-14121.
Bach, A., Chi, C. N., Pang, G. F., Olsen, L., Kristensen, A. S., Jemth, P. & Stromgaard, K. (2009) Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction, Angew Chem Int Ed. 48, 9685-9689.
Krintel, C., Frydenvang, K., Olsen, L., Kristensen, M. T., de Barrios, O., Naur, P., Francotte, P., Pirotte, B., Gajhede, M. & Kastrup, J. S. (2012) Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2, Biochem J. 441, 173-178.
Nørholm, A.-B., Francotte, P., Olsen, L., Krintel, C., Frydenvang, K., Goffin, E., Challal, S., Danober, L., Botez-Pop, I., Lestage, P., Pirotte, B. & Kastrup, J. S. (2013) Synthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold, J Med Chem. 56, 8736-8745.

Selected references on Histone Demethylases:

Lohse, B., Nielsen, A. L., Kristensen, J. B. L., Helgstrand, C., Cloos, P. A. C., Olsen, L., Gajhede, M., Clausen, R. P. & Kristensen, J. L. (2011) Targeting histone lysine demethylases by truncating the histone 3 tail to obtain selective substrate-based inhibitors, Angew Chem Int Ed. 50, 9100-9103.
Kristensen, L. H., Nielsen, A. L., Helgstrand, C., Lees, M., Cloos, P., Kastrup, J. S., Helin, K., Olsen, L. & Gajhede, M. (2012) Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor, FEBS Journal. 279, 1905-1914.
Nielsen, A. L., Kristensen, L. H., Stephansen, K. B., Kristensen, J. B. L., Helgstrand, C., Lees, M., Cloos, P., Helin, K., Gajhede, M. & Olsen, L. (2012) Identification of catechols as histone-lysine demethylase inhibitors, FEBS Lett. 586, 1190-1194.
Hopkinson, R. J., Tumber, A., Yapp, C., Chowdhury, R., Aik, W., Che, K. H., Li, X. S., Kristensen, J. B. L., King, O. N. F., Chan, M. C., Yeoh, K. K., Choi, H., Walport, L. J., Thinnes, C. C., Bush, J. T., Lejeune, C., Rydzik, A. M., Rose, N. R., Bagg, E. A., McDonough, M. A., Krojer, T. J., Yue, W. W., Ng, S. S., Olsen, L., Brennan, P. E., Oppermann, U., Muller, S., Klose, R. J., Ratcliffe, P. J., Schofield, C. J. & Kawamura, A. (2013) 5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation, Chem Sci. 4, 3110-3117.

 

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