Plants vs. GPCRs: A workflow for ligand discovery from an extract library illustrated by dopamine receptors.

Plants have served as source of medicines for millennia, yielding structurally diverse and biologically active small molecules with high therapeutic potential. Many plant natural products modulate the most druggable target class, G protein-coupled receptors (GPCRs). Traditionally, the discovery of these plant natural products relies on ethnopharmacological guidance and trial-and-error based medicinal use. However, the vast majority of plants remain unexplored for their pharmacological and therapeutic potential. This suggests that an unbiased approach based on screening plant extracts at GPCRs of interest may allow for the discovery of novel ligands and pharmacological properties. In this perspective, we first discuss the historical and ongoing role of plant natural products in GPCR drug discovery, using dopamine receptors, a key subfamily of Class A GPCRs involved in neurological disorders like Parkinson's disease and schizophrenia, as a well-documented example. To explore untapped pharmacological potential, we conducted an unbiased screen of 240 extracts from plants collected in California for activity at the dopamine D5 receptor (DRD5), identifying 14 hits (5.83%) with agonist-like activity. This indicates the presence of potentially novel dopaminergic plant natural products. We propose a modern, multidimensional workflow encompassing hit identification, prioritization, and dereplication via tandem mass spectrometry and molecular networking, integrated with bioassay-guided fractionation to advance hits to isolated bioactive natural products. Together, these findings and this approach highlight the underexplored potential of plant-derived chemical diversity as a feasible source of new GPCR modulators.