Department of Drug Design and Pharmacology > Employees
Birgit Isabel Gaiser
Medicinal Chemistry Research
2100 København Ø
G protein-coupled receptors (GPCRs) constitute the largest family of membrane-bound receptors. They are activated by a broad variety of endogenous ligands and thereby mediate various cellular responses. As a consequence, they are in involved in many pathophysiological processes, making them attractive targets in drug therapy. Most GPCR drug discovery efforts to date have focused on preventing or mimicking the orthosteric interaction. However, it has been difficult to obtain subtype selective GPCR ligands due to the fact that orthosteric binding sites are generally highly conserved and due to the general lack of structural information on allosteric binding pockets.
A recent computational study on the pathway and mechanism of ligand binding to GPCRs revealed that ligands pause at several transient low affinity binding sites on their way to the orthosteric binding site. Such meta-stable binding sites are generally less conserved compared to the orthosteric binding sites, and thus we envision to attain high affinity, receptor subtype selective GPCR ligands by linking two identical pharmacophores to simultaneously target the orthosteric and a meta-stable binding site.