Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons
Abstract
:1. Introduction
2. Results and Discussion
2.1. Computational Modeling of FTO Ligand Binding Site and Virtual Screening
2.2. Enzyme Activity Inhibition
2.3. Protein Binding of Compounds
2.4. Neuronal Survival Experiments
2.5. Penetration of the FTO Inhibitors Through the Blood-Brain Barrier in Artificial In Vitro Model
3. Materials and Methods
3.1. Compounds
3.2. FTO Protein
3.3. Computational Modeling
3.4. Protein Binding Study Using Microscale Thermophoresis
3.5. Enzyme Inhibition Assay
3.6. Primary Cultures of Midbrain Dopamine Neurons and m6A Regulator Treatment
3.7. Artificial Blood–Brain Barrier Model
3.8. Quantification and Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | Compound Structure | ΔG (kcal/mol) | DE |
---|---|---|---|
1 | −7.37 | 0.53 | |
2 | −7.70 | 0.51 | |
3 | −7.03 | 0.50 | |
4 | −8.78 | 0.49 | |
5 | −7.17 | 0.48 | |
6 | −9.45 | 0.47 | |
7 * | −6.53 | 0.44 | |
8 * | −4.78 | 0.32 |
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Selberg, S.; Yu, L.-Y.; Bondarenko, O.; Kankuri, E.; Seli, N.; Kovaleva, V.; Herodes, K.; Saarma, M.; Karelson, M. Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons. Int. J. Mol. Sci. 2021, 22, 4537. https://doi.org/10.3390/ijms22094537
Selberg S, Yu L-Y, Bondarenko O, Kankuri E, Seli N, Kovaleva V, Herodes K, Saarma M, Karelson M. Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons. International Journal of Molecular Sciences. 2021; 22(9):4537. https://doi.org/10.3390/ijms22094537
Chicago/Turabian StyleSelberg, Simona, Li-Ying Yu, Olesja Bondarenko, Esko Kankuri, Neinar Seli, Vera Kovaleva, Koit Herodes, Mart Saarma, and Mati Karelson. 2021. "Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons" International Journal of Molecular Sciences 22, no. 9: 4537. https://doi.org/10.3390/ijms22094537