虚拟发现调节昼夜节律的黑激素受体配体
Reed M Stein1, Hye Jin Kang2, John D McCorvy2,3
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Nature
|February 11, 2020
概括
研究人员通过选数百万个分子发现了新的MT1选择性反向激动剂. 这些化合物有效地重置小鼠的昼夜节律, 为睡眠和情绪障碍提供新的治疗潜力.
科学领域:
- 神经科学
- 药理学
- 时间生物学
背景情况:
- 通过MT1和MT2受体同步昼夜节律.
- MT1和MT2受体是睡眠障碍和抑郁症的目标.
- 在体内活跃的MT1选择性配体的有限可用性阻碍了研究和药物开发.
研究的目的:
- 为了确定新的,活跃的MT1选择性配体.
- 探索调节黑色素受体生物学的新化学型.
- 进一步了解每日节律的调节.
主要方法:
- 虚拟选超过1.5亿个分子与MT1晶体结构.
- 基于结构的优化高等级的对接化合物.
- 在生理周期重新训练的小鼠模型中对合成的配体进行体内测试.
主要成果:
- 发现强大的MT1选择性逆激动剂 (470 pM至6 μM).
- 在拓上不相关的化学类型的识别.
- 通过MT1选择性逆激应剂证明了小鼠昼夜时钟 (1.3-1.5小时) 的相位推进.
结论:
- 大型库的基于结构的选可以产生新的活体体.
- 选择性MT1逆激动剂是生物节律调节的有希望的途径.
- 这些发现为开发针对昼夜节律障碍的向治疗开辟了新的可能性.
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