Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2024-10-29 DOI:10.1016/j.cell.2024.10.001

Jun Yang, Tianjun Zhao, Junping Fan, Huaibin Zou, Guangyi Lan, Fusheng Guo, Yaocheng Shi, Han Ke, Huasheng Yu, Zongwei Yue, Xin Wang, Yingjie Bai, Shuai Li, Yingjun Liu, Xiaoming Wang, Yu Chen, Yulong Li, Xiaoguang Lei

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Abstract

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

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在结构指导下发现用于治疗肝病且不会引起瘙痒的胆汁酸衍生物

慢性瘙痒是一种使人衰弱的症状，严重影响胆汁淤积症等肝病患者的生活质量。胆汁酸（BA）激活人类 G 蛋白偶联受体 MRGPRX4 (hX4) 与促进胆汁淤积性瘙痒有关。然而，其详细的内在机制仍然难以捉摸。在这里，我们发现了胆汁淤积症患者瘙痒症状中升高的 3-硫酸化胆汁酸。我们解析了hX4-Gq与3-磷酸化脱氧胆酸（DCA-3P）复合物的低温电子显微镜结构，3-磷酸化脱氧胆酸是内源性3-硫酸化脱氧胆酸（DCA-3S）的模拟物。该结构揭示了 MRGPR 家族蛋白中前所未有的配体结合口袋，突出了 BA 上的 3-hydroxyl (3-OH) 基团在激活 hX4 中的关键作用。在这一结构信息的指导下，我们设计并开发了化合物 7（C7），一种缺少 3-OH 的 BA 衍生物。值得注意的是，C7 能有效缓解肝病模型中的肝损伤和肝纤维化，同时显著减轻瘙痒的副作用。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.