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通过人工智能驱动的下一代查,发现了针对TLR4-TLR4同位素化的pyrazolo[1,5-a]pyrimidine衍生物

Yao-Yao Jiang¹, Shuai-Ting Yan¹, Shan-Zhuo Zhang²

¹State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China.

European journal of medicinal chemistry

|October 10, 2024

概括

研究人员使用人工智能发现TH023,一种针对托尔类受体4 (TLR4) 分解的新药. 这种化合物有效地降低了细胞和小鼠的炎症,显示出治疗TLR4相关疾病的前景.

科学领域:

免疫学免疫学免疫学
药物发现药物发现药物发现
计算化学计算化学

背景情况:

收费类受体4 (TLR4) 信号传递对先天免疫非常重要.
准TLR4通路为相关疾病提供了治疗潜力.

研究的目的:

使用人工智能识别TLR4-TLR4*同位分化的小分子抑制剂.
发现和优化一种新型的pyrazolo[1,5-a]pyrimidine衍生物作为TLR4抑制剂.

主要方法:

人工智能 (AI) 驱动的选使用HelixVS和HelixDock.
结构与活动关系 (SAR) 研究.
在体外测试 (NF-κB激活,氧化生产) 和体内研究 (败血小鼠模型).
分子动力学 (MD) 模拟.

主要成果:

鉴定了pyrazolo[1,5-a]pyrimidine衍生物的TH023. 这就是它.
TH023抑制了LPS刺激的NF-κB激活 (IC50 = 0.354 μM) 和氧化的产生 (IC50 = 1.61 μM).
MD模拟显示TH023稳定了TLR4-MD-2并破坏了TLR4-TLR4*的关联.
在败血症小鼠中,TH023减少了肺损伤和促炎细胞因子.

结论:

使用HelixDock的人工智能驱动的药物发现对于准蛋白质与蛋白质相互作用 (PPI) 有效.
TH023代表了TLR4介导的炎症性疾病的有前途的治疗候选者.
针对TLR4二分化提供了一种新的策略来调节先天免疫反应.

关键词:

由人工智能驱动的虚拟选.抗炎药物抗炎药物抗炎药物均质化 (homodimerization) 是一种同质化的过程.模拟MD的模拟方法皮拉佐[1,5-a]皮里米丁是一种 TLR4−TLR4 的时间.

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