人工智能驱动的迁移学习和生成模型（TransGenGRU）使新型天然瓜木酚内酯倍半萜衍生物成为有效的NLRP3抑制剂的药物发现

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-10-10 DOI:10.1021/acs.jmedchem.5c01663

Weijiang Lin, Ping Wang, Yishu Zhang, Wenyu Lu, Meng Yang, Zhenzhen Zhu, Xunkai Yin, Jiahao Lv, Zhe Zheng, Shulan Mei, Yan Huang, Wenzhuo Xu, Xiaoqian Peng, Yang Hu, Yinan Zhang, Qi Lv, Jian Liu, Lihong Hu

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引用次数: 0

摘要

NLRP3炎性小体被认为是先天免疫的重要介质，它可以调节促炎细胞因子的成熟。目前，几种天然产物已被证实具有有效的NLRP3抑制作用，并与NLRP3具有新的结合机制。本文提出了一个人工智能驱动的模型（TransGenGRU）来生成具有NLRP3抑制活性的新型天然产物。通过TransGenGRU建模，鉴定出两种瓜木酚内酯倍半萜（A3和A8）具有中等的NLRP3抑制活性。然后，通过详细的结构优化，E1显示出最有效的NLRP3抑制活性（IC50 = 24.42 nM），对NLRP3炎症小体的抑制作用与NLRP3/pro-caspase-1/ASC的组装有关。值得注意的是，E1被证实与完全不同于MCC950的Cys280发生共价不可逆相互作用。此外，E1在体内也显示出强大的抗炎活性，良好的DMPK谱和低hERG毒性。因此，E1被认为是一种新的有效的NLRP3抑制剂。

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AI-Driven Transfer Learning and Generative Model (TransGenGRU) Enables the Drug Discovery of Novel Natural Guaianolide Sesquiterpene Derivatives as Potent NLRP3 Inhibitors

The NLRP3 inflammasome is recognized as a critical mediator of innate immunity, which can regulate the maturation of proinflammatory cytokines. Nowadays, several natural products have been confirmed to exhibit potent NLRP3 inhibitory effects and possess novel binding mechanisms with NLRP3. Herein, an AI-driven model (TransGenGRU) is proposed to generate novel natural products with NLRP3 inhibitory activities. Through the modeling of TransGenGRU, two guaianolide sesquiterpenoids (A3 and A8) are identified to possess moderate NLRP3 inhibitory activities. Then, through detailed structure optimization, E1 demonstrates the most potent NLRP3 inhibitory activity (IC₅₀ = 24.42 nM), and the inhibitory effect on the NLRP3 inflammasome is correlated to the assembly of NLRP3/pro-caspase-1/ASC. Notably, E1 is confirmed to covalent-irreversibly interact with Cys280 that is totally different from MCC950. Besides, E1 also demonstrates potent anti-inflammatory activity in vivo, favorable DMPK profiles, and low hERG toxicity. Thus, E1 has been considered a novel and potent NLRP3 inhibitor.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.