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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\u2009+\u2009CIB2\u2009+\u2009TMIE 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.<\/jats:p>","DOI":"10.1038\/s42003-025-07943-x","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T11:39:13Z","timestamp":1747136353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of druggable binding sites and small molecules as modulators of TMC1"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-3345","authenticated-orcid":false,"given":"Pedro","family":"De-la-Torre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0266-3310","authenticated-orcid":false,"given":"Claudia","family":"Mart\u00ednez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5172-2316","authenticated-orcid":false,"given":"Paul","family":"Gratias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5471-4813","authenticated-orcid":false,"given":"Matthew","family":"Mun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5742-4926","authenticated-orcid":false,"given":"Paula","family":"Santana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurunisa","family":"Akyuz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2076-6818","authenticated-orcid":false,"given":"Artur A.","family":"Indzhykulian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-1189","authenticated-orcid":false,"given":"David","family":"Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"7943_CR1","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1002\/ar.22579","volume":"295","author":"S. 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