超大型虚拟查揭示了神经调节性孤儿受体GPR139的强有力的激动剂
Israel Cabeza de Vaca1, Boris Trapkov2, Ling Shen3
1Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Nature communications
|December 9, 2025
概括
研究人员使用计算对接来发现用于神经精神疾病的新型G蛋白结合受体 (GPCR) GPR139激活剂. 结构引导优化产生了强效化合物,证明了可行的药物发现策略.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- G蛋白结合受体 (GPCR) GPR139是神经精神疾病的潜在治疗标.
- 了解GPR139的功能和结构对于药物开发至关重要.
研究的目的:
- 调查基于结构的药物发现对GPR139.9的可行性.
- 使用计算和实验方法识别新的GPR139激动剂.
主要方法:
- 针对GPR139结合部位的2.35亿个化合物的大规模计算对接.
- 对GPR139激动性排名最高的化合物的实验性评估.
- 结构引导优化和冷电子显微镜 (cryo-EM) 用于复杂结构的确定.
- 对AlphaFold3进行评估,以建模GPCR-连接物相互作用.
主要成果:
- 确定了五种完全的GPR139激动剂,其强度从160nM到3.6μM.
- 由结构引导的优化导致了一个非常强大的GPR139激动剂.
- 低温电磁波证实了优化对接体的预测结合模式.
- 一种激动剂在小鼠中表现出行为效应,而AlphaFold3对这个研究不足的GPCR显示出有限的效用.
结论:
- 高分辨率的GPCR结构与广泛的虚拟查相结合,加速了药物发现.
- 这项研究提供了强大的GPR139激动剂,并对GPCR信号传递提供了宝贵的见解.
- 基于结构的方法对于针对像GPR139.9这样的孤儿GPCR是有效的.
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