A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts

Subtype selectivity
and functional bias are vital in current drug
discovery for G protein-coupled receptors (GPCRs) as selective and
biased ligands are expected to yield drug leads with optimal on-target
benefits and minimal side-effects. However, structure-based design
and medicinal chemistry exploration remain challenging in part because
of highly conserved binding pockets within subfamilies. Herein, we
present an affinity mass spectrometry approach for screening herbal
extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring
aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias
toward G protein signaling for which key residues were identified,
and it showed comparable in vivo efficacy for food
intake suppression and weight loss as the antiobesity drug, lorcaserin.
Our study establishes an efficient approach to discovering novel GPCR
ligands by exploring the largely untapped chemical space of natural
products.