Molecular Docking of 6-shogaol and Curcumin on DNMT1 and LSD1 As Potential Agents for Thalassemia Treatment

Joko Setyono, Sekar Cahyo Nurani, Muhamad Salman Fareza, Arif Fadlan, Sarmoko Sarmoko


Beta-thalassemia therapy is developed by increasing γ-globin production which binds to α-globin to form haemoglobin fetal (HbF). Meanwhile, DNA methyltransferase 1 (DNMT1) and lysine specific demethylase 1 (LSD1) play an important role in silencing the HbF gene by inhibiting the production of HbF and inducing haemoglobin subunit alpha (HbA) expression. 6-Shogaol and curcumin induce HbF by inhibiting signal transducer and activator of transcription 3 (STAT3) expression. Therefore, this study predicts the interaction between 6-shogaol and curcumin on DNMT1 and LSD1. The protein structure of DNMT1 (3SWR) and LSD1 (6KGP) was prepared by removing the water molecules, while the validation step was performed by separating protein from native ligands (sinefungin for 3SWR and flavine-adenine dinucleotide (FAD) for 6KGP) in new protein data bank files. Furthermore, the protein was docked with a native ligand to obtain grid box coordinates, while the root means standard deviation (RMSD) was calculated from the conformation results of the validation process. 6-Shogaol and curcumin were docked with coordinates of the validation results, and the best conformation was visualized with Discovery Studio. The validation step results in the RMSD value of 0.861Å and 1.410Å for DNMT1 and LSD1, respectively. The binding affinity of 6-shogaol and curcumin on DNMT1 was -6.5 kcal/mol and -8.0 kcal/mol, respectively. Furthermore, the binding affinity of 6-shogaol and curcumin on LSD1 was -8.2 kcal/mol and -10.1 kcal/mol, respectively. Amino acid residues found in DNMT1 interaction include Gly1147, Phe1145, Glu1168, Asn1278, Pro1225, Leu1151, Val1580, Ala1579, Asn1578, Trp1170, and Ala1579; meanwhile, Val288, Ser289, Arg310, Gly285, Thr624, Leu659, Lys661, Arg316, Leu625, Tyr761, Trp751, Gly330, and Leu659 were found in LSD1. This study showed that curcumin has the potential to inhibit DNMT1 as well as LSD1 proven by lower bonding energy and stronger bond types compared to sinefungin and FAD native ligands and other DNMT1 and LSD1 inhibitors.


beta-thalassemia; DNMT1; LSD1; molecular docking

Full Text:



[1] E. Fibach and E. A. Rachmilewitz, “Pathophysiology and treatment of patients with beta-thalassemia - an update. [version 1; peer review: 2 approved],” F1000Res., vol. 6, p. 2156, Dec. 2017.
DOI: 10.12688/f1000research.12688.1

[2] P. A. Wahidiyat, T. T. Sari, L. D. Rahmartani, I. Setianingsih, S. D. Iskandar, A. M. Pratanata, I. Yapiy, M. Yosia, and F. Tricta, “An insight into Indonesian current thalassaemia care and challenges,” ISBT Sci. Ser., vol. 15, no. 3, pp. 334–341, Aug. 2020.
DOI: 10.1111/voxs.12544

[3] L. Rujito, “Talasemia : Genetik Dasar dan Pengelolaan Terkini,” Zenodo, 2019.
Available: googlescholar

[4] A. Basak and V. G. Sankaran, “Regulation of the fetal hemoglobin silencing factor BCL11A.,” Ann. N. Y. Acad. Sci., vol. 1368, no. 1, pp. 25–30, Mar. 2016.
DOI: 10.1111/nyas.13024

[5] M. Suzuki, M. Yamamoto, and J. D. Engel, “Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies.,” Mol. Cell. Biol., vol. 34, no. 19, pp. 3560–3569, Oct. 2014.
DOI: 10.1128/MCB.00714-14

[6] J. Setyono, A. H. Sadewa, E. Meiyanto, and M. Mustofa, “Curcumin and 6-Shogaol Increase Hemoglobin F Levels by Inhibiting Expression of STAT3 mRNA Gene in K562 Line Cell,” Indian Journal of Public Health Research & Development, Jan. 2020.
DOI: 10.37506/v11/i1/2020/ijphrd/194002

[7] M. D. Hanwell, D. E. Curtis, D. C. Lonie, T. Vandermeersch, E. Zurek, and G. R. Hutchison, “Avogadro: An Advanced Semantic Chemical Editor, Visualization, and Analysis Platform.,” J. Cheminform., vol. 4, no. 1, pp. 17, Aug. 2012.
DOI: 10.1186/1758-2946-4-17

[8] O. Trott and A. J. Olson, “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.,” J. Comput. Chem., vol. 31, no. 2, pp. 455–461, Jan. 2010.
DOI: 10.1002/jcc.21334

[9] A. Wlodawer, W. Minor, Z. Dauter, and M. Jaskolski, “Protein crystallography for non-crystallographers, or how to get the best (but not more) from published macromolecular structures.,” The FEBS Journal, vol. 275, no. 1, pp. 1–21. Dec. 2007.
DOI: 10.1111/j.1742-4658.2007.06178.x

[10] H, Hashimoto and X. Cheng, “Structure of human DNMT1 (residues 600-1600) in complex with Sinefungin.,” 2011.
DOI: 10.2210/pdb3SWR/pdb

[11] H. Niwa, S. Sato, N. Handa, T. Sengoku, T. Umehara, and S. Yokoyama, “Development and structural evaluation of N-alkylated trans-2-phenylcyclopropylamine-based LSD1 inhibitors.,” ChemMedChem, vol.5, no. 9, pp. 787–793. 2020.
DOI: 10.1002/cmdc.202000014

[12] D. Ramírez and J. Caballero, “Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data?,” Molecules, vol. 23, no. 5, Apr. 2018.
DOI: 10.3390/molecules23051038

[13] S. Forli, R. Huey, M. E. Pique, M. F. Sanner, D. S. Goodsell, and A. J. Olson, “Computational protein-ligand docking and virtual drug screening with the AutoDock suite.,” Nat. Protoc., vol. 11, no. 5, pp. 905–919, May 2016.
DOI: 10.1038/nprot.2016.051

[14] W. J. Lee and B. T. Zhu, “Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols.,” Carcinogenesis, vol. 27, no. 2, pp. 269–277, Feb. 2006.
DOI: 10.1093/carcin/bgi206

[15] D. Li, R. Wang, Y. Yan, G. Jin, G. Song, D. Ma, and L. Guan, “In-silico investigations into natural products as nonnucleoside DNA methyltransferase 1 inhibitors for treating epi-mutation in gastric cancer,” Tropical Journal of Pharmaceutical Research, Mar. 2017.
DOI: 10.4314/tjpr.v16i2.25

[16] J. K. Day, A. M. Bauer, C. DesBordes, Y. Zhuang, B.-E. Kim, L. G. Newton, V. Nehra, K. M. Forsee, R. S. MacDonald, C. Besch-Williford, T. H.-M. Huang, and D. B. Lubahn, “Genistein alters methylation patterns in mice.,” J. Nutr., vol. 132, no. 8 Suppl, p. 2419S–2423S, Aug. 2002.
DOI: 10.1093/jn/132.8.2419S

[17] Z. Liu, S. Liu, Z. Xie, R. E. Pavlovicz, J. Wu, P. Chen, J. Aimiuwu, J. Pang, D. Bhasin, P. Neviani, J. R. Fuchs, C. Plass, P.-K. Li, C. Li, T. H.-M. Huang, L.-C. Wu, L. Rush, H. Wang, D. Perrotti, G. Marcucci, and K. K. Chan, “Modulation of DNA methylation by a sesquiterpene lactone parthenolide.,” J. Pharmacol. Exp. Ther., vol. 329, no. 2, pp. 505–514, May 2009.
DOI: 10.1124/jpet.108.147934

[18] T. Xie, J. Yu, W. Fu, Z. Wang, L. Xu, S. Chang, E. Wang, F. Zhu, S. Zeng, Y. Kang, and T. Hou, “Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: a molecular simulation study.,” Phys. Chem. Chem. Phys., vol. 21, no. 24, pp. 12931–12947, Jun. 2019.
DOI: 10.1039/C9CP02024A

[19] E. Cuyàs, J. Gumuzio, J. Lozano-Sánchez, D. Carreras, S. Verdura, L. Llorach-Parés, M. Sanchez-Martinez, E. Selga, G. J. Pérez, F. S. Scornik, R. Brugada, J. Bosch-Barrera, A. Segura-Carretero, Á. G. Martin, J. A. Encinar, and J. A. Menendez, “Extra virgin olive oil contains a phenolic inhibitor of the histone demethylase LSD1/KDM1A.,” Nutrients, vol. 11, no. 7, Jul. 2019.
DOI: 10.3390/nu11071656

[20] E. Cuyàs, J. Gumuzio, S. Verdura, J. Brunet, J. Bosch-Barrera, B. Martin-Castillo, T. Alarcón, J. A. Encinar, Á. G. Martin, and J. A. Menendez, “The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes.,” Aging (Albany, NY), vol. 12, no. 6, pp. 4794–4814, Mar. 2020.
DOI: 10.18632/aging.102887


  • There are currently no refbacks.