Zhang Bingjie, Zhao Simeng, Yang Dehua, Wu Yiran, Xin Ye, Cao Haijie, Huang Xi-Ping, Cai Xiaoqing, Sun Wen, Ye Na, Xu Yueming, Peng Yao, Zhao Suwen, Liu Zhi-Jie, Zhong Guisheng, Wang Ming-Wei, Shui Wenqing
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.
ACS Cent Sci. 2020 Feb 26;6(2):213-225. doi: 10.1021/acscentsci.9b01125. Epub 2020 Jan 23.
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 receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT without activating the 5-HT or 5-HT receptors. Remarkably, this novel ligand exhibited exclusive bias toward G protein signaling for which key residues were identified, and it showed comparable 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.
亚型选择性和功能偏向性在当前针对G蛋白偶联受体（GPCR）的药物发现中至关重要，因为选择性和偏向性配体有望产生具有最佳靶标效应和最小副作用的药物先导物。然而，基于结构的设计和药物化学探索仍然具有挑战性，部分原因是亚家族内的结合口袋高度保守。在此，我们提出一种亲和质谱方法，用于筛选草药提取物以鉴定GPCR（5-羟色胺受体）的活性配体。使用这种方法，我们发现了一种天然存在的阿朴啡1857，它对激活5-羟色胺具有很强的选择性，而不会激活5-羟色胺或5-羟色胺受体。值得注意的是，这种新型配体对G蛋白信号传导表现出独特的偏向性，并且确定了关键残基，它在抑制食物摄入和减肥方面显示出与抗肥胖药物氯卡色林相当的功效。我们的研究建立了一种通过探索天然产物中很大程度上未被开发的化学空间来发现新型GPCR配体的有效方法。
