鉴定新型卢潘类型三类物质作为与RAR相关的孤儿受体马 (RORγ) 的逆激素
Patrik F Schwarz1,2, Alexander F Perhal1, Famke Guder3
1Department of Pharmaceutical Sciences, Division of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
Journal of natural products
|July 28, 2025
概括
研究人员发现了一种新的五环三类化合物,作为与视网膜酸相关的孤儿受体玛 (RORγ) 逆agonist,为自身免疫性疾病治疗提供了潜在的潜力.
科学领域:
- 药用化学 医学化学
- 分子药理学分子药理学
- 免疫学 免疫学 免疫学
背景情况:
- 与网红酸相关的孤儿受体玛 (RORγ) 是自身免疫性疾病治疗的关键标.
- 对RORγ的逆激动剂为牛皮,类风湿性关节炎和多发性硬化症等疾病提供了有前途的治疗策略.
研究的目的:
- 通过基于结构的虚拟查来识别新的RORγ反向激动剂.
- 描述已识别的化合物及其类型的活性和结合.
主要方法:
- 基于结构的虚拟选,以识别潜在的RORγ逆agonists.
- 试验室测定包括光酶记者测定 (Gal4-RORγ和全长RORγ) 和热转移测定.
- 实时定量PCR评估目标基因下调.
- 分子对接和位点定向突变发生,用于结合模式分析.
主要成果:
- 一种新的狼类型的五环三胺,化合物15被确定为一种强大的RORγ逆agonist (IC50值为0.4μM和0.9μM).
- 与贝鲁林酸相比,化合物15显示出更高的功效和疗效.
- 两种类型 (15.2和15.3) 也表现出RORγ逆agonist活性,所有三种都降低了RORγ基因的调节.
- 结合试验证实了RORγ联体结合域的稳定,通过对接和突变发生解明了不同的结合模式.
结论:
- 五环三类化合物代表了开发新型RORγ逆agonists的可行支架.
- 化合物15及其类型对RORγ介导的自身免疫性疾病具有治疗潜力.
- 详细的结构和机制洞察力获得了RORγ反向激励.
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