A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts
Authors: Ming-Wei Wang
Xiaoqing Cai
Bingjie Zhang
Wen Sun
Guisheng Zhong
Dehua Yang
Yiran Wu
Yao Peng
Zhi-Jie Liu
Wenqing Shui
Simeng Zhao
Yueming Xu
Haijie Cao
Xi-Ping Huang
Suwen Zhao
Ye Xin
Na Ye
Journal: ACS Central Science (2020)
Discipline: CHEMISTRY
Keywords: drug discovery; G protein-coupled receptors (GPCRs); subtype selectivity; functional bias; ligands
Affiliations: iHuman Institute, ShanghaiTech University, Shanghai 201210, China., The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Department of Pharmacology, NIMH Psychoactive Drug Screening Program, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States., University of Chinese Academy of Sciences, Beijing 100049, China., Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China., School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China., School of Pharmacy, Fudan University, Shanghai 201203, China.

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. 

Retracted: No

PubPeer comments:
 Figure 5G shows  representative tissue images . * Red boxes: In the iWAT row, the two Vehicle tissues appear to look identical. There were 9 mice per group, so maybe the authors could explain what happened here, please?  , 
 Dear Dr. Elisabeth Bik, We appreciate your comment very much. Upon receipt, we conducted an investigation relative to your concerns and found that in Figure 5 (the iWAT row), the two vehicle tissues are indeed identical. This was caused by a cut-paste error during figure preparation. The original picture is attached herewith for your information. We are very sorry for this mistake and will make a new Figure 5 to be published as an erratum in the journal concerned. We also enclose our original experiment record showing individual data obtained from each animal (n=9) at autopsy. Thank you very much again for your comment and critique that alert us to take necessary steps to avoid such mistakes in the future. Best regards, Guisheng Zhong Ming-Wei Wang Wenqing Shui    , 
 Correction, May 2020: https: pubs.acs.org doi 10.1021 acscentsci.0c00448  After publication of the original manuscript, we found that, in Figure 5G (the iWAT row), the two vehicle tissues were identical. This was caused by a cutu2013paste error during figure preparation. The original picture, original Figure 5G, and corrected Figure 5G are shown below. We also attached the corrected Figure 5. We apologize for this error and will take necessary steps to avoid such mistakes in the future. ,