G protein-Coupled Receptors (GPCRs) as Drug Targets

G protein-coupled receptors (GPCRs) constitute a large and diverse superfamily of membrane proteins that play a crucial role in cellular communication and signal transduction. The human genome encodes approximately 800 GPCRs that are activated by a wide range of different ligands, including hormones, neurotransmitters, peptides, and sensory stimuli (e.g., light, taste, smell). Due to their vital role in numerous physiological processes as well as their cell-surface location, GPCRs are highly important drug targets – in fact, approximately 34% of all marketed drugs target GPCRs.

GPCRs are commonly grouped into classes based on their sequence homology, structural features, and functional characteristics. Structurally, all GPCRs have a characteristic seven α-helical transmembrane (7TM) domain. The majority of GPCRs belong to the class A of GPCRs and are monomeric GPCRs that have their orthosteric ligand binding sites in the 7TM domain. Our research group has extensive experience from studying multiple class A GPCRs, and we currently have a PhD student studying the class A gonadotropin-releasing hormone receptor (GnRHR).

In recent years, our main GPCR of interest has been the γ-amino butyric acid B (GABA-B) receptor, which, together with the metabotropic glutamate receptors (mGluRs), the calcium-sensing receptor (CaSR), taste receptors and orphan receptors, constitute the class C of GPCRs. GABA and glutamate are the main inhibitory and excitatory neurotransmitters of the central nervous system, and the GABA-B receptor and mGluRs are highly interesting pharmacological targets, particularly in the treatment of neurological and psychiatric disorders. Ligands that act on these receptors can influence synaptic transmission and neuronal excitability, and may offer potential benefits in conditions like anxiety, depression, and schizophrenia. Class C GPCRs are obligatory homo- or heterodimeric proteins and, in addition to the 7TM domain, they are characterised by their large extracellular domains that host their orthosteric ligand binding sites for agonists and antagonists. Class C GPCRs furthermore have allosteric ligand binding sites within or between their transmembrane domains. Drugs that are allosteric modulators (NAMs and PAMs) can provide new mechanisms of action that are distinct from traditional orthosteric drugs, potentially leading to innovative treatments for diseases where conventional approaches have been ineffective. Drugs that are allosteric modulators can also preferentially influence specific signalling pathways (biased signalling), offering the possibility to tailor therapeutic effects by selectively activating beneficial pathways while avoiding harmful ones.

In our projects, we are using our toolbox of molecular modelling and in vitro methods to identify new orthosteric and allosteric ligands and to study the molecular mechanisms of actions of orthosteric and allosteric ligands interacting with GPCRs.