鉴定药物可结合部位和小分子作为TMC1调节器
Pedro De-la-Torre1, Claudia Martínez-García2, Paul Gratias1
1Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and Ear, Boston, MA, USA.
bioRxiv : the preprint server for biology
|June 3, 2024
概括
研究人员开发了一种新的选方法,通过调节机械转导 (MET) 通道来寻找保护听力和平衡的药物. 这种方法确定了具有MET调节活性的新型化合物和FDA批准的药物,为治疗内耳功能障碍提供了希望.
科学领域:
- 内耳生理学 内耳生理学
- 机械敏感的离子通道
- 药物发现 药物发现
背景情况:
- 内耳感觉毛细胞对于听力和平衡至关重要,依靠机械传导 (MET) 通道 (TMC1/2) 将机械刺激转化为电信号.
- 耳毒药物通过MET通道进入头发细胞,从而损害头发细胞,导致听力和平衡障碍.
- 对小分子与MET通道相互作用的有限理解阻碍了自身保护疗法的发展.
研究的目的:
- 开发和验证基于结构的选管道,用于识别基于TMC的MET通道的新型调节器.
- 研究小分子调制剂与MET复合物的相互作用部位和机制.
- 发现新的治疗化合物,以预防药物诱导的内耳损伤.
主要方法:
- 集成的3D药建模,TMC1+CIB2+TMIE复合体的分子动力学模拟,以及分子对接.
- 实验验证使用染料吸收试验在培养的耳扩展器中进行实验验证.
- 自由能量估计以确定药物结合部位和关键相互作用残留物.
主要成果:
- 查管道成功识别了具有MET调节活性的新型化合物和FDA批准的药物.
- 在通道孔内确定了三个潜在的药物结合部位,以及关键的脂和氨基酸.
- TMIE蛋白被描述为MET复合物的灵活组成部分,并与TMEM16蛋白发现了与TMEM16蛋白共享的联结特征.
结论:
- 开发的基于结构的选管道对于发现机械敏感离子通道调节器是有效的.
- 这种方法为TMC通道药理学和潜在的自我保护治疗策略提供了宝贵的见解.
- 这些发现为开发新的治疗方法铺平了道路,以保护听力和平衡功能.
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