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Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations

文献类型：期刊论文

作者Gao, Yang3,4; Zhu, Haoran3,4; Gao, Li-Xin2; Xu, Gao-Ya1,2; Lin, Jing3,4; Sun, Lujie3,4; Li, Wei3,4; Li, Jia2; Fu, Wei3,4
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2025-12-15
卷号131页码:15
关键词Thyroid hormone receptor beta (THR-beta) Agonists Metabolic-associated steatohepatitis (MASH) Molecular dynamics simulations
ISSN号0968-0896
DOI10.1016/j.bmc.2025.118397
通讯作者Li, Jia(jli@simm.ac.cn) ; Fu, Wei(wfu@fudan.edu.cn)
英文摘要Thyroid hormone receptor (3 (THR-(3) plays a crucial role in regulating lipid metabolism, steatohepatitis, and liver fibrosis. The approval of Resmetirom has demonstrated the therapeutic potential of THR-(3 agonism in treating metabolic-associated steatohepatitis (MASH). Therefore, investigating the mechanism of THR-(3 activation is essential for understanding its mode of action and further research. In this study, we report a newly designed THR-(3 agonist, D4, which exhibits superior in vitro activity, with a Ki value of 257.3 nM, providing a valuable tool for exploring receptor activation. To gain mechanistic insights, we conducted 500 ns molecular dynamics (MD) simulations on three systems: THR-(3 bound to agonist D4, THR-(3 bound to a known antagonist 6, and apo THR-(3 (ligand-free). A detailed analysis of the structural stability and activation mechanism of these systems was performed. Our findings suggest a novel activation mechanism in which a dynamic salt bridge relay, mediated by Loop-H11-H12, stabilizes the active state of the receptor. In addition, key hydrophobic interaction formed by antagonist and carbon chain of Arg438 was found to be crucial for ligands to switch from agonist to antagonist.
WOS关键词THYROID-HORMONE RECEPTORS ; SELECTIVE THYROMIMETICS ; ANALOGS ; ANTAGONIST ; LIGANDS
资助项目National Natural Science Foundation of China[82574323] ; National Natural Science Foundation of China[82273853] ; Science and Technology Commis-sion of Shanghai Municipality[25JS2830100]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001584924400001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/321594]  
专题中国科学院上海药物研究所
通讯作者Li, Jia; Fu, Wei
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Fudan Univ, Minhang Hosp, Shanghai 201203, Peoples R China
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Yang,Zhu, Haoran,Gao, Li-Xin,et al. Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2025,131:15.
APA Gao, Yang.,Zhu, Haoran.,Gao, Li-Xin.,Xu, Gao-Ya.,Lin, Jing.,...&Fu, Wei.(2025).Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations.BIOORGANIC & MEDICINAL CHEMISTRY,131,15.
MLA Gao, Yang,et al."Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations".BIOORGANIC & MEDICINAL CHEMISTRY 131(2025):15.

入库方式： OAI收割

来源：上海药物研究所

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