Identification of druggable binding sites and small molecules as modulators of TMC1
Abstract 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...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07943-x |
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| author | Pedro De-la-Torre Claudia Martínez-García Paul Gratias Matthew Mun Paula Santana Nurunisa Akyuz Wendy González Artur A. Indzhykulian David Ramírez |
| author_facet | Pedro De-la-Torre Claudia Martínez-García Paul Gratias Matthew Mun Paula Santana Nurunisa Akyuz Wendy González Artur A. Indzhykulian David Ramírez |
| author_sort | Pedro De-la-Torre |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-c70fab267be74b15b375bc49ec523418 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-c70fab267be74b15b375bc49ec5234182025-08-20T02:25:12ZengNature PortfolioCommunications Biology2399-36422025-05-018112210.1038/s42003-025-07943-xIdentification of druggable binding sites and small molecules as modulators of TMC1Pedro De-la-Torre0Claudia Martínez-García1Paul Gratias2Matthew Mun3Paula Santana4Nurunisa Akyuz5Wendy González6Artur A. Indzhykulian7David Ramírez8Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and EarDepartamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de ConcepciónDepartment of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and EarDepartment of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and EarFacultad de Ingeniería, Instituto de Ciencias Aplicadas, Universidad Autónoma de ChileDepartment of Neurobiology, Harvard Medical SchoolCenter for Bioinformatics, Simulations and Modelling (CBSM), University of TalcaDepartment of Otolaryngology - Head and Neck Surgery, Harvard Medical School and Mass Eye and EarDepartamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de ConcepciónAbstract 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.https://doi.org/10.1038/s42003-025-07943-x |
| spellingShingle | Pedro De-la-Torre Claudia Martínez-García Paul Gratias Matthew Mun Paula Santana Nurunisa Akyuz Wendy González Artur A. Indzhykulian David Ramírez Identification of druggable binding sites and small molecules as modulators of TMC1 Communications Biology |
| title | Identification of druggable binding sites and small molecules as modulators of TMC1 |
| title_full | Identification of druggable binding sites and small molecules as modulators of TMC1 |
| title_fullStr | Identification of druggable binding sites and small molecules as modulators of TMC1 |
| title_full_unstemmed | Identification of druggable binding sites and small molecules as modulators of TMC1 |
| title_short | Identification of druggable binding sites and small molecules as modulators of TMC1 |
| title_sort | identification of druggable binding sites and small molecules as modulators of tmc1 |
| url | https://doi.org/10.1038/s42003-025-07943-x |
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