Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach
Introduction: Epithelial-mesenchymal transition (EMT) is a process of epithelial transformation into mesenchymal cells. It is also a process that contributes to the progression of fibrosis and cancer metastasis. Transforming growth factor-beta (TGF-²), as a potent inducer of EMT, has therefore becam...
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| Format: | Article |
| Language: | English |
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Universiti Putra Malaysia Press
2023
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| Online Access: | http://psasir.upm.edu.my/id/eprint/107414/ http://psasir.upm.edu.my/id/eprint/107414/1/107414.pdf |
| _version_ | 1848864890104578048 |
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| author | Chun Hao, Ong Chau Ling, Tham Harith, Hanis Hazeera Firdaus, Nazmi Ahmad Israf, Daud |
| author_facet | Chun Hao, Ong Chau Ling, Tham Harith, Hanis Hazeera Firdaus, Nazmi Ahmad Israf, Daud |
| author_sort | Chun Hao, Ong |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Introduction: Epithelial-mesenchymal transition (EMT) is a process of epithelial transformation into mesenchymal cells. It is also a process that contributes to the progression of fibrosis and cancer metastasis. Transforming growth factor-beta (TGF-²), as a potent inducer of EMT, has therefore became a potential therapeutic target. However, clinical developments of TGF-² inhibitors have been un-successful due to safety risks. Hence, drug repurposing of existing safe-to-use drugs could over-come this issue. Methods: In this study, the TGF-² receptor type 1 (ALK5) was selected as the target protein. Molecular docking was performed using known ALK5 inhibitors as positive con- trols. Clinical drugs with similar binding affinity and amino acid interaction were selected for in vitro experimental validation. Results: ALK5 inhibitor demonstrated binding affinities ranging from -11.2 to -9.5 kcal/mol. Analysis of amino acid interaction revealed that Val219, Ala230, Lys232, and Leu340 amino acid residues are crucial for bind- ing. Subsequent screening of clinically approved drugs against ALK5 showed top five potential drugs (ergotamine, telmisartan, saquinavir, indinavir, and nelfinavir). The selected drugs were tested in TGF-²1-induced normal human bronchial epithelial cell line, BEAS-2B. Western blot analysis showed that the drugs did not exhibit inhibitory effects on the downregulation of epithelial proteins (E-cadherin) and upregulation of mesenchymal proteins (vimentin and ±-smooth muscle actin). Conclusion: Based on these experimental outcome, it is postulated that the results from mo- lecular docking were false positives. The tested drugs in this study could serve as negative controls in future screening against ALK5 protein. |
| first_indexed | 2025-11-15T13:56:00Z |
| format | Article |
| id | upm-107414 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T13:56:00Z |
| publishDate | 2023 |
| publisher | Universiti Putra Malaysia Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-1074142024-11-04T03:15:54Z http://psasir.upm.edu.my/id/eprint/107414/ Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach Chun Hao, Ong Chau Ling, Tham Harith, Hanis Hazeera Firdaus, Nazmi Ahmad Israf, Daud Introduction: Epithelial-mesenchymal transition (EMT) is a process of epithelial transformation into mesenchymal cells. It is also a process that contributes to the progression of fibrosis and cancer metastasis. Transforming growth factor-beta (TGF-²), as a potent inducer of EMT, has therefore became a potential therapeutic target. However, clinical developments of TGF-² inhibitors have been un-successful due to safety risks. Hence, drug repurposing of existing safe-to-use drugs could over-come this issue. Methods: In this study, the TGF-² receptor type 1 (ALK5) was selected as the target protein. Molecular docking was performed using known ALK5 inhibitors as positive con- trols. Clinical drugs with similar binding affinity and amino acid interaction were selected for in vitro experimental validation. Results: ALK5 inhibitor demonstrated binding affinities ranging from -11.2 to -9.5 kcal/mol. Analysis of amino acid interaction revealed that Val219, Ala230, Lys232, and Leu340 amino acid residues are crucial for bind- ing. Subsequent screening of clinically approved drugs against ALK5 showed top five potential drugs (ergotamine, telmisartan, saquinavir, indinavir, and nelfinavir). The selected drugs were tested in TGF-²1-induced normal human bronchial epithelial cell line, BEAS-2B. Western blot analysis showed that the drugs did not exhibit inhibitory effects on the downregulation of epithelial proteins (E-cadherin) and upregulation of mesenchymal proteins (vimentin and ±-smooth muscle actin). Conclusion: Based on these experimental outcome, it is postulated that the results from mo- lecular docking were false positives. The tested drugs in this study could serve as negative controls in future screening against ALK5 protein. Universiti Putra Malaysia Press 2023 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/107414/1/107414.pdf Chun Hao, Ong and Chau Ling, Tham and Harith, Hanis Hazeera and Firdaus, Nazmi and Ahmad Israf, Daud (2023) Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach. Malaysian Journal of Medicine and Health Sciences, 19 (5). art. no. 3. 15 - 23. ISSN 1675-8544; eISSN: 2636-9346 https://medic.upm.edu.my/upload/dokumen/2023091810365503_MJMHS_1210.pdf 10.47836/mjmhs.19.5.4 |
| spellingShingle | Chun Hao, Ong Chau Ling, Tham Harith, Hanis Hazeera Firdaus, Nazmi Ahmad Israf, Daud Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title | Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title_full | Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title_fullStr | Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title_full_unstemmed | Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title_short | Drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| title_sort | drug repurposing of clinically approved drugs to target epithelial-mesenchymal transition using molecular docking approach |
| url | http://psasir.upm.edu.my/id/eprint/107414/ http://psasir.upm.edu.my/id/eprint/107414/ http://psasir.upm.edu.my/id/eprint/107414/ http://psasir.upm.edu.my/id/eprint/107414/1/107414.pdf |