Department of Pharmaceutical Chemistry
Marbacher Weg 8, 35032 Marburg
+49-6421 28 25908
Research Area Small molecules are frequently used both in nature and therapeutically to modulate the activity of the protein they bind to. Yet, many aspects of small-molecule:protein interactions are poorly understood. For instance, ligand polypharmacology, i.e. binding to multiple proteins, often comes as a surprise, although frequently it is precisely the reason for a drug's efficacy or its side effects. We investigate ligand:protein interactions in atomistic detail using chemoinformatic methods, such as docking and molecular dynamics (MD) simulations. The main aim is to predict molecules with tailored properties, such as selectivity, efficacy or biased signaling. In order to reach this goal, we also develop strategies to explore chemical space. The research spans method development, basic research, and applications. Currently the investigations focus on G protein-coupled receptors (GPCRs), but we also work on kinases, proteases and protein arginine methyltransferases (PRMTs).
in silico synthesis
1. Gunera J, Baker JG, van Hilten N, Rosenbaum DM, Kolb P (2020) Structure-based Discovery of Novel Ligands for the Orexin 2 Receptor. J. Med. Chem., just accepted
2. Scharf MM, Bünemann M, Baker JG, Kolb P (2019) Comparative docking to distinct G protein-coupled receptor conformations exclusively yields ligands with agonist efficacy. Mol. Pharmacol. 96: 851-861
3. Chevillard F, Stotani S, Karawajczyk A, Hristeva S, Pardon E, Steyaert J, Tzalis D, Kolb P (2019) Interrogating dense ligand chemical space with a forward-synthetic library. Proc. Natl. Acad. Sci. U.S.A. 116: 11496-11501