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

作者：Bingjie Zhang, Simeng Zhao, Dehua Yang, Yiran Wu, Xin Ye, 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 · 发表于：ACS Central Science · 年份：2020 · DOI：10.1021/acscentsci.9b01125 · 被引用次数：47 · 研究领域：Receptor Mechanisms and Signaling、Computational Drug Discovery Methods、Neuropeptides and Animal Physiology

High Resolution Image Download MS PowerPoint Slide 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-HT 2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT 2C without activating the 5-HT 2A or 5-HT 2B 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.