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.

中文翻译：

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从筛选草药提取物中发现的一种新的针对G蛋白偶联受体的G蛋白偏置和亚型选择性激动剂。

在目前的G蛋白偶联受体（GPCR）药物发现中，亚型的选择性和功能性偏见至关重要，因为预期选择性和偏向的配体会产生具有最佳靶标获益和最小副作用的药物线索。然而，基于结构的设计和药物化学探索仍然具有挑战性，部分原因是亚家族中高度保守的结合口袋。在这里，我们提出了一种用于筛选草药提取物以鉴定GPCR的有效配体（5-HT2C受体）的亲和质谱方法。使用这种方法，我们发现了天然存在的阿福啡1857，它在不激活5-HT2A或5-HT2B受体的情况下对激活5-HT2C表现出很强的选择性。值得注意的是，这种新的配体对G蛋白信号显示出排他性偏向，从而鉴定出关键残基，与抗肥胖药lorcaserin相比，在抑制食物摄入和减轻体重方面显示出可比的体内功效。我们的研究通过探索天然产物中尚未开发的化学空间，建立了一种发现新型GPCR配体的有效方法。