Molecular Metabolic Pharmacology in the Frimurer Group

The Frimurer Group investigates how small molecules and drugs interact with target proteins to modulate their function, with special interest in translational pharmacology and rational design of next generation drugs.

Research focus

Identification of new biological target molecules is needed to develop new drugs to treat diabetes and obesity. Potential target proteins are often discovered as e.g. gene hits in large genetic or epigenetic studies or through single cell transcriptomic analysis. However, protein-based biochemical assays and pharmacological tool compounds (drug candidates) to validate these target proteins are needed.

The core focus of the Frimurer Group is related to translational pharmacology and rational design of next generation drugs. We use structure-based design technologies to discover ligands that can be developed into pharmacological tool compounds and early drug candidates which is used to characterize the physiological role of food and metabolite sensing receptors as well as other metabolic target proteins associated with the regulation of glucose homeostasis, adipose function and are considered high value targets for the treatment of metabolic diseases. A major goal is to determine the mechanistic action of new drug candidates in the context of human disease and establish novel pharmacological paradigms that will result in the rational design of next generation drugs.

Main findings

“Full monty of family B GPCRs”
Published in Nature Chemical Biology in 2017 this article describes the new structures of the glucagon-like peptide-1 (GLP-1) and glucagon receptors in complex with peptide and nonpeptide ligands that provide a comprehensive, detailed picture of the molecular mechanisms of action of family B GPCRs.

“Model-Based Discovery of Synthetic Agonists for the Zn2+-Sensing G-Protein-Coupled Receptor 39 (GPR39) Reveals Novel Biological Functions”
Published in Journal of Medicinal Chemistry in 2017 this study uses a homology model-based approach to identify small-molecule pharmacological tool compounds for the G-protein-coupled receptor 39 and identifies GPR39 as a novel regulator of gastric somatostatin secretion.

“Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening”
Published in Structure in 2015 this study describes the development of a data-driven optimization protocol, which integrates mutational data and structural information from multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol to determine the binding conformation of AR231453, a small-molecule agonist, in the GPR119 receptor.

Staff of the Frimurer Group

Group leader: Associate Professor Thomas Frimurer.

The Frimurer Group