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

Abstract

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.

• Authors: Bingjie Zhang, Simeng Zhao, Dehua Yang, Yiran Wu, Ye Xin, Haijie Cao, Xi-Ping Huang, Xiaoqing Cai, Wen Sun, Na Ye, Yueming Xu, Yao Peng, Suwen Zhao, Zhi-Jie Liu, Guisheng Zhong, Ming-Wei Wang, Wenqing Shui
• Journal: ACS central science (ACS Cent Sci) Vol. 6 Issue 2 Pg. 213-225 (Feb 26 2020) ISSN: 2374-7943 [Print] United States
• PMID: 32123739 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.