Drug Repurposing of Clinically Approved Drugs to Target Epithelial-mesenchymal Transition Using Molecular Docking Approach
https://doi.org/10.47836/mjmhs.19.5.4
- Author:
Chun Hao Ong
1
;
Chau Ling Tham
1
;
Hanis Hazeera Harith
1
;
Nazmi Firdaus
1
;
Daud Ahmad Israf
1
Author Information
1. Department of Biomedical Science, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Seri Kembangan, Malaysia
- Publication Type:Journal Article
- Keywords:
Drug Repurposing, Epithelial-mesenchymal transition, Molecular Docking, Transforming growth factor-bet
- From:Malaysian Journal of Medicine and Health Sciences
2023;19(No.5):15-23
- CountryMalaysia
- Language:English
-
Abstract:
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-β), as a potent inducer of EMT, has therefore became a potential therapeutic target. However,
clinical developments of TGF-β 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-β receptor type 1 (ALK5)
was selected as the target protein. Molecular docking was performed using known ALK5 inhibitors as positive controls. 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 binding. 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-β1-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
α-smooth muscle actin). Conclusion: Based on these experimental outcome, it is postulated that the results from molecular docking were false positives. The tested drugs in this study could serve as negative controls in future screening
against ALK5 protein.
- Full text:11.2023my1606.pdf
