Shin Seo Hyun, Hur Gihyun, Kim Na Ra, Park Jung Han Yoon, Lee Ki Won, Yang Hee
Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea.
Bio-MAX Institute, Seoul National University, Seoul, 08826, Republic of Korea.
Food Funct. 2023 Feb 21;14(4):1869-1883. doi: 10.1039/d2fo03466b.
As a type of stress hormone, glucocorticoids (GCs) affect numerous physiological pathways by binding to the glucocorticoid receptor (GR) and regulating the transcription of various genes. However, when GCs are dysregulated, the resulting hypercortisolism may contribute to various metabolic disorders, including obesity. Thus, attempts have been made to discover potent GR antagonists that can reverse excess-GC-related metabolic diseases. Phytochemicals are a collection of valuable bioactive compounds that are known for their wide variety of chemotypes. Recently, various computational methods have been developed to obtain active phytochemicals that can modulate desired target proteins. In this study, we developed a workflow comprising two consecutive quantitative structure-activity relationship-based machine learning models to discover novel GR-antagonizing phytochemicals. These two models collectively identified 65 phytochemicals that bind to and antagonize GR. Of these, nine commercially available phytochemicals were validated for GR-antagonist and anti-obesity activities. In particular, we confirmed that demethylzeylasteral, a phytochemical of the Radix, exhibits potent anti-obesity activity through GR antagonism.
作为一种应激激素，糖皮质激素（GCs）通过与糖皮质激素受体（GR）结合并调节各种基因的转录来影响众多生理途径。然而，当GCs失调时，由此产生的皮质醇增多症可能会导致包括肥胖在内的各种代谢紊乱。因此，人们一直在尝试发现能够逆转与GC过量相关的代谢疾病的有效GR拮抗剂。植物化学物质是一类有价值的生物活性化合物，以其多种化学类型而闻名。最近，已经开发了各种计算方法来获得能够调节所需靶蛋白的活性植物化学物质。在本研究中，我们开发了一个工作流程，该流程包括两个连续的基于定量构效关系的机器学习模型，以发现新型GR拮抗植物化学物质。这两个模型共同鉴定出65种与GR结合并拮抗GR的植物化学物质。其中，9种市售植物化学物质的GR拮抗剂和抗肥胖活性得到了验证。特别是，我们证实了作为Radix植物化学物质的去甲基紫铆亭通过GR拮抗作用表现出强大的抗肥胖活性。
