Identification of novel TMEM16A blockers through integrated virtual screening, molecular dynamics, and experimental studies
Issued Date
2025-12-01
Resource Type
eISSN
20452322
Scopus ID
2-s2.0-105003883634
Journal Title
Scientific Reports
Volume
15
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Scientific Reports Vol.15 No.1 (2025)
Suggested Citation
Sangkhawasi M., Pitaktrakul W., Khumjiang R., Shigeta Y., Muanprasat C., Hengphasatporn K., Rungrotmongkol T. Identification of novel TMEM16A blockers through integrated virtual screening, molecular dynamics, and experimental studies. Scientific Reports Vol.15 No.1 (2025). doi:10.1038/s41598-025-99751-w Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/109946
Title
Identification of novel TMEM16A blockers through integrated virtual screening, molecular dynamics, and experimental studies
Corresponding Author(s)
Other Contributor(s)
Abstract
The calcium-activated chloride channel TMEM16A is a promising drug target for treating hypertension, secretory diarrheas, and various cancers, including head and neck cancer. Despite its potential, no FDA-approved drugs have provided the structural basis for directly inhibiting TMEM16A. This study aims to identify a novel pore-blocker of TMEM16A by integrating virtual screening, molecular dynamics simulations, and in vitro studies. Using the calcium-bound structure of TMEM16A with and without the pore-blocker 1PBC, we performed virtual screening on nearly 90,000 compounds from the ChemDiv database. Approximately 67% of these compounds demonstrated better binding affinity than 1PBC. Among the top 20 compounds selected for short-circuit current assays using human lung adenocarcinoma cells (Calu-3), compounds N066-0059, N066-0060, and N066-0067 inhibited TMEM16A activity with IC50 values of 0.24 µM, 0.41 µM, and 0.48 µM, respectively, which was lower than that of a positive control Ani9 (9 µM). Due to its highest potency in electrophysiological assays, N066-0059 was subjected to mechanistic studies. Molecular dynamics simulations elucidated its binding stability and strength, showing superior performance to 1PBC over 500 ns with 3 replicates. This study advances TMEM16A-targeted drug development, offering new insights for anticancer therapies.