Emerging paradigms for target discovery of traditional medicines: A genome-wide pan-GPCR perspective

Traditional medicines serve not only as an integral part of medical treatments prescribed by healthcare providers but also as a fundamental reservoir for novel molecular scaffolds. However, gaps remain in our understanding of the mechanisms underlying their activity. A superfamily of membrane proteins, G protein-coupled receptors (GPCRs), have been demonstrated to be potential targets for several compounds isolated from traditional medicines. Given that GPCRs serve as targets for approximately one-third of all marketed drugs, they may be compelling targets for repurposing traditional medicines. Despite this potential, research investigating their activity or potential ligands across GPCRome, the library of human GPCRs, is scarce. Drawing on the functional and structural knowledge presently available, this review contemplates prospective trends in GPCR drug discovery, proposes innovative strategies for investigating traditional medicines, and highlights ligand screening approaches for identifying novel drug-like molecules. To discover bioactive molecules from traditional medicines that either directly bind to GPCRs or indirectly modify their function, a genome-wide pan-GPCR drug discovery platform was designed for the identification of bioactive components and targets, and the evaluation of their pharmacological profiles. This platform aims to aid the exploration of all-sided relations between traditional medicines and GPCRome using advanced high-throughput screening techniques. We present various approaches used by many, including ourselves, to illuminate the previously unexplored aspects of traditional medicines and GPCRs.