G Protein-coupled Receptors: One of the Most Important Drug Discovery Targets

Abstract

G protein-coupled receptors are considered the most widely investigated drug discovery targets. They are the largest family of receptors with almost 800 genes in humans. Different types of ligands can activate these receptors, such as catecholamines, nucleotides, lipids, and gut microbiota, where some ligands could be bitopic. Nevertheless, some receptors have internal ligands bound to them. Activated G protein-coupled receptors have complex signaling pathways that are involved in almost all bodily functions. Furthermore, they constitute a large percentage of Food and Drug Administration marketed drugs and global share of drugs, in addition to a great proportion of drugs currently in clinical trials targeting these receptors. The approved G protein-coupled receptors targeted drugs and potential drugs are involved in the management of many diseases including cancer, inflammatory diseases, diabetes mellitus, hypertension, obesity, pain, and diseases of the central nervous system. Only 10% of G protein-coupled receptors are targeted. Different pharmacological approaches have been considered in drug discovery of these receptors including polypharmacology, allosteric modulators, biased agonism, tethered agonism, and pharmacogenomics. Advances in the technologies are promising to help in the discovery of new targets. The review's aim is to discuss the importance of G protein-coupled receptors as drug discovery targets.