De-la-Torre Pedro, Martínez-García Claudia, Gratias Paul, Mun Matthew, Santana Paula, Akyuz Nurunisa, González Wendy, Indzhykulian Artur A, Ramírez David
Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and Ear, Boston, MA, USA.
Facultad de Ciencias Básicas, Universidad del Atlántico, Barranquilla, Colombia.
Commun Biol. 2025 May 13;8(1):742. doi: 10.1038/s42003-025-07943-x.
Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed of TMC1/2 proteins. However, the therapeutic use of ototoxic drugs, such as aminoglycosides and cisplatin, which can enter hair cells through MET channels, often leads to profound auditory and vestibular dysfunction. To date, our understanding of how small-molecule modulators interact with TMCs remains limited, hampering the discovery of novel drugs. Here, we propose a structure-based drug screening approach, integrating 3D-pharmacophore modeling, molecular dynamics simulations of the TMC1 + CIB2 + TMIE complex, and experimental validation. Our pipeline successfully identified three potential drug-binding sites within the TMC1 pore, phospholipids, and key amino acids involved in the binding of several compounds, as well as FDA-approved drugs that reduced dye uptake in cultured cochlear explants. Our pipeline offers a broad application for discovering modulators for mechanosensitive ion channels.
我们的听力和维持平衡的能力依赖于内耳感觉毛细胞的正常功能，这些毛细胞通过由TMC1/2蛋白组成的机械-电换能（MET）通道将机械刺激转化为电信号。然而，耳毒性药物，如氨基糖苷类和顺铂，可通过MET通道进入毛细胞，其治疗用途常常导致严重的听觉和前庭功能障碍。迄今为止，我们对小分子调节剂如何与TMC相互作用的理解仍然有限，这阻碍了新型药物的发现。在此，我们提出一种基于结构的药物筛选方法，整合了3D药效团建模、TMC1 + CIB2 + TMIE复合物的分子动力学模拟以及实验验证。我们的流程成功地在TMC1孔内确定了三个潜在的药物结合位点、磷脂以及参与几种化合物结合的关键氨基酸，还确定了能减少培养的耳蜗外植体中染料摄取的FDA批准药物。我们的流程为发现机械敏感离子通道的调节剂提供了广泛的应用。
