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Research in Pharmaceutical Sciences، جلد ۲۰، شماره ۳، صفحات ۳۹۲-۴۰۷
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عنوان انگلیسی Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer
چکیده انگلیسی مقاله Background and purpose : The Fat mass and obesity-associated protein (FTO) plays a significant role in esophageal cancer by regulating N6-methyladenosine (m6A) modification. FTO inhibition has shown potential in cancer therapies but remains underexplored. This study aimed to identify a safer, FDA-approved compound for FTO inhibition that can be used in combination with chemotherapy drugs. Experimental approach: FDA-approved drugs were screened from the Zinc15 database using AutoDock Vina against the 3D structure of FTO (PDB ID: 3LFM). Discovery Studio software was used to determine binding interactions. The GROMACS package was used for molecular dynamics simulations. A non-toxic concentration was determined through an MTT assay on KYSE-30 esophageal cancer cells. The ELISA assay was used to measure the m6A levels in RNA. Findings/ Results: Four compounds, ergotamine, midazolam, digoxin, and loratadine, were identified. Loratadine (ΔG: -8.9) formed stable interactions with FTO, specifically with residues Ser229, Tyr109, Leu109, Val229, and His231. Molecular dynamic simulations of the FTO-loratadine complex revealed higher RMSD fluctuations (0.4-0.6 nm), but the system remained stable overall. RMSF analysis showed similar fluctuation patterns in all three systems, indicating that loratadine did not affect protein structure stability. MM/PBSA calculations revealed powerful binding energy for the FTO-loratadine complex (-135.73 kJ/mol), driven by favorable van der Waals interactions. KYSE-30 cells treated with loratadine (100 μM), m6A levels in KYSE-30 cells compared to the control group were significantly elevated at a non-toxic concentration. Conclusion and implications : Loratadine is a promising, low-toxic FTO inhibitor that could complement chemotherapy for esophageal cancer.
کلیدواژه‌های انگلیسی مقاله AutoDock Vina,Drug repurposing,Esophageal cancer,Fat mass and obesity associated protein,Molecular dynamics simulation,N6-methyl adenosine.
نویسندگان مقاله | Zeinab Mohammadi
Metabolic Disorders Research Center, Biomedical Research Institute, Golestan University of Medical Sciences, Gorgan, Iran. Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran.


| Marie Saghaeian Jazi
Metabolic Disorders Research Center, Biomedical Research Institute, Golestan University of Medical Sciences, Gorgan, Iran. Department of Clinical Biochemistry, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.


| Seyyed Mehdi Jafari
Metabolic Disorders Research Center, Biomedical Research Institute, Golestan University of Medical Sciences, Gorgan, Iran. Department of Clinical Biochemistry, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.


| Seyyed Mostafa Mir
Metabolic Disorders Research Center, Biomedical Research Institute, Golestan University of Medical Sciences, Gorgan, Iran. Department of Clinical Biochemistry, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.


| Jahanbakhsh Asadi
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.


| Massoud Amanlou


نشانی اینترنتی http://rps.mui.ac.ir/index.php/jrps/article/view/2313
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