The goal of my research group is to improve atomic-level understanding of protein-ligand interactions using computer models. We mainly focus our efforts on G protein-coupled receptors (GPCRs), which are involved in essential physiological processes and the targets of numerous therapeutic drugs. Using physics-based models, we model on how small molecules interact with GPCRs and thereby modulate their function with the goal to develop novel strategies for drug development.
The aims of my ongoing research are to design GPCR ligands with tailored signaling and selectivity profiles as well as to demonstrate that structure-based virtual screening can identify modulators of challenging drug targets and novel (allosteric) binding sites. To accomplish these goals, we develop strategies for structure-based virtual screening using a combination of cheminformatics, structure prediction, molecular docking, and molecular dynamics simulations. All our projects are driven by predictions based on computer models, which are evaluated experimentally in our own laboratory or in collaboration with international research groups.
Our projects are funded by grants from the European and Swedish research councils. We are part of the Dept. of Cell and Molecular Biology and the Science for Life Laboratory at Uppsala university.
Areas of interest: Structure-based drug design, molecular docking, virtual screening, molecular dynamics simulations, free energy calculations, protein structure prediction, chemical libraries, medicinal chemistry, G protein-coupled receptors
Jens Carlsson, PI
Duy Duc Vo
Kennedy J.A., Ballante F., Johansson J.R., Milligan G., Linda SundströmL., Nordqvist A, and Carlsson J.(2018) Structural characterization of agonist binding to protease-activated receptor 2 through mutagenesis and computational modelling. ACS Pharmacol Transl Sci 1, 119-133.
Jaiteh M., Zeifman A., Saarinen M., Svenningsson P., Brea J.M., Loza M.I., and Carlsson J.(2018) Docking screens for dual inhibitors of disparate drug targets for Parkinson’s disease. J Med Chem61, 5269-5278.
Rudling A., Gustafsson R., Almlöf I., Homan E., Scobie M., Warpman Berglund U., Helleday T., Stenmark P., and Carlsson J.(2017) Fragment-based discovery and optimization of enzyme inhibitors by docking of commercial chemical space. J Med Chem60, 8160-8169.
Petersen J., Wright S.C., Rodríguez D., Matricon P., Lahav N., Vromen A., Friedler A., Strömqvist J., Wennmalm S., Carlsson J., and Schulte G. (2017) Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Nat Comm8, 226.
Matricon P., Ranganathan A., Warnick E., Gao Z.G., Rudling A., Lambertucci C., Marucci G., Ezzati A., Jaiteh M., Dal Ben D., Jacobson K.A., and Carlsson J.(2017) Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A2Aadenosine receptor binding site. Sci Rep7, 6398.
Ranganathan A., Heine P., Rudling A, Plückthun A., Kummer L., Carlsson J. (2016) Ligand discovery for a peptide-binding GPCR by structure-based screening of fragment- and lead-like chemical libraries. ACS Chem Biol12, 735-745.
Rodríguez D., Chakraborty S., Warnick E., Crane S., Gao Z.G., O’Connor R., Jacobson K.A. and Carlsson J. (2016) Structure-based screening of uncharted chemical space for atypical adenosine receptor agonists. ACS Chem Biol11, 2763-2772.
Ranganathan A., Stoddart L.A., Hill S.J., Carlsson J.(2015) Fragment-based discovery of subtype selective adenosine receptor ligands from homology models. J Med Chem58, 9578-9590.
Ranganathan A., Dror R.O., and Carlsson J.(2014) Insights into the role of Asp792.50in β2adrenergic receptor activation from molecular dynamics simulations. Biochemistry53, 7283-7296.
Rodríguez D., Brea J., Loza M.I., and Carlsson J.(2014) Structure-based discovery of selective serotonin 5-HT1Breceptor ligands. Structure22, 1140-1151.