Exploring structure-based drug discovery of GPCRs beyond the orthosteric binding site

G-protein coupled receptors (GPCRs) are the largest family of druggable targets. In recent years, GPCR structural biology has made great advances, revealing the three-dimensional structures of many GPCRs and their interactions with ligands, proteins, and membrane components, which also have inspired a surge of structure-based drug discovery campaigns. This article provides a comprehensive summary of the currently available structural insights into the allosteric pockets of GPCRs and their regulatory mechanisms governing GPCR conformational changes. Furthermore, this article also presents several structure-inspired studies that utilize both orthosteric and allosteric modulation to discover small molecular modulators targeting GPCRs. The article emphasizes the promising potential of drug discovery targeting GPCR allosteric sites, while acknowledging the challenges arising from the limited structural information regarding the lipids and cholesterols in membrane. Finally, the article discusses the future prospects of using large-scale or focused compound libraries to discover novel chemotypes, as well as the application of artificial intelligence (AI) in structure-based virtual screening (SBVS) against GPCRs.