Unveiling the flavonoid and theaflavin compounds from the genus Camellia in Vietnam towards inhibiting Keap1-Nrf2 by in silico screening method
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Author
Keywords:
Machine learning
Keap1-Nrf2 inhibitor
Camellia genus
molecular docking
in silico
Abstract
Species from the Camellia genus have long been shown antioxidant properties through the quenching of free radicals. This study employed an in silico virtual screening approach, integrating machine learning algorithms to predict the antioxidant potential of five species from the Camellia genus, namely Camellia sinensis, Camellia quephongensis, Camellia oleifera, Camellia amplexicaulis, and Camellia japonica, by evaluating the capacity to inhibit Keap1-Nrf2 complex, indirectly enhance Nrf2 expression. Four machine learning algorithms including Support Vector Machines (SVM), Random Forests (RF), Extreme Gradient Boosting (XGBoost), and Multilayer Perceptron (MLP)-were utilized to build a classification model for predicting compound activity. Based on the top-performing model, 33 promising compounds were identified. These Nrf2-activating compounds were further analyzed through molecular docking with the Keap1-Nrf2 complex (PDB ID: 2FLU). The docking results highlighted four compounds with the most favorable binding affinities: camellianoside (-10.4 kcal/mol), theaflavin-3-gallate (-9.9 kcal/mol), theaflavin-3'-gallate (-9.8 kcal/mol), and camelliaside B (-9.7 kcal/mol).
References
-
[1] C. Khanh and N. H. Nam, “Oxidative Stress and Disease”, Journal of Pediatrics, vol. 15, no. 1, Jun. 2023, doi: https://doi.org/10.52724/tcnk.v15i1.176.
[2] Huchzermeyer, E. Menghani, P. Khardia, and A. Shilu, “Metabolic Pathway of Natural Antioxidants, Antioxidant Enzymes and ROS Providence”, Antioxidants, vol. 11, no. 4, p. 761, Apr. 2022, doi: https://doi.org/10.3390/antiox11040761.
[3] T. Dinkova-Kostova et al., “Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants”, Proceedings of the National Academy of Sciences, vol. 99, no. 18, pp. 11908–11913, Aug. 2002, doi: 10.1073/pnas.172398899.
[4] Ogura et al., “Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains”, Proceedings of the National Academy of Sciences, vol. 107, no. 7, pp. 2842–2847, Jan. 2010, doi: 10.1073/pnas.0914036107.
[5] Yamamoto et al., “Physiological significance of reactive cysteine residues of KEAP1 in determining NRF2 activity”, Molecular and Cellular Biology, vol. 28, no. 8, pp. 2758–2770, Feb. 2008, doi: 10.1128/mcb.01704-07.
[6] O. Tkachev, E. B. Menshchikova, and N. K. Zenkov, “Mechanism of the Nrf2/Keap1/ARE signaling system”, Biochemistry (Moscow), vol. 76, no. 4, pp. 407–422, Apr. 2011, doi: 10.1134/s0006297911040031.
[7] M. U. Ahmed, L. Luo, A. Namani, X. J. Wang, and X. Tang, “Nrf2 signaling pathway: Pivotal roles in inflammation”, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1863, no. 2, pp. 585–597, Feb. 2017, doi: https://doi.org/10.1016/j.bbadis.2016.11.005.
[8] Chen, M. Xiao, S. Hu, and M. Wang, “Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer”, Frontiers in Oncology, vol. 14, Apr. 2024, doi: 10.3389/fonc.2024.1381467.
[9] Pant, D. Dasgupta, A. Tripathi, and K. Pyaram, “Beyond antioxidation: KEAP1–NRF2 in the development and effector functions of adaptive immune cells”, ImmunoHorizons, vol. 7, no. 4, pp. 288–298, Apr. 2023, doi: 10.4049/immunohorizons.2200061.
[10] Sova and L. Saso, “Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review”, Drug Design Development and Therapy, vol. Volume 12, pp. 3181–3197, Sep. 2018, doi: 10.2147/dddt.s172612.
[11] Silva, “Tecfidera (dimethyl fumarate) for MS | Uses, side effects, and more”, Multiple Sclerosis News Today, Dec. 13, 2023. https://multiplesclerosisnewstoday.com/tecfidera-dimethyl-fumarate-multiple-sclerosis [Accessed Sep. 9, 2024].
[12] Robledinos-Antón, R. Fernández-Ginés, G. Manda, and A. Cuadrado, “Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development”, Oxidative Medicine and Cellular Longevity, vol. 2019, pp. 1–20, Jul. 2019, doi: https://doi.org/10.1155/2019/9372182.
[13] W. Kensler et al., “Keap1-Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane”, Topics in current chemistry, vol. 329, pp. 163–177, 2013, doi: https://doi.org/10.1007/128_2012_339.
[14] Unni, P. Deshmukh, G. Krishnappa, P. Kommu, and B. Padmanabhan, “Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1”, The FEBS journal, vol. 288, no. 5, pp. 1599–1613, Mar. 2021, doi: https://doi.org/10.1111/febs.15485.
[15] D. Zhang and M. Hannink, “Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress”, Molecular and Cellular Biology, vol. 23, no. 22, pp. 8137–8151, Oct. 2003, doi: https://doi.org/10.1128/mcb.23.22.8137-8151.2003.
[16] A. Abed, S. Lee, and L. Hu, “Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction”, Bioorganic & Medicinal Chemistry, vol. 28, no. 6, p. 115343, Mar. 2020, doi: https://doi.org/10.1016/j.bmc.2020.115343.
[17] Wen, G. Thorne, L. Hu, M. S. Joy, and L. M. Aleksunes, “Activation of NRF2 signaling in HEK293 cells by a First-in-Class direct KEAP1-NRF2 inhibitor”, Journal of Biochemical and Molecular Toxicology, vol. 29, no. 6, pp. 261–266, Feb. 2015, doi: 10.1002/jbt.21693.
[18] Zhao, C. Li, S. Wang, and X. Song, “Green tea (Camellia sinensis): A review of its phytochemistry, pharmacology, and toxicology”, Molecules, vol. 27, no. 12, p.3909, 2022, doi: 10.3390/molecules27123909
[19] Musial, A. Kuban-Jankowska, and M. Gorska-Ponikowska, “Beneficial properties of green tea catechins”, International Journal of Molecular Sciences, vol. 21, no. 5, p. 1744, Mar. 2020, doi: 10.3390/ijms21051744.
[20] M. Teixeira and C. Sousa, “A review on the biological activity of camellia species”, Molecules, vol. 26, no. 8, p. 2178, Apr. 2021, doi: 10.3390/molecules26082178.
[21] Trott and A. J. Olson, “AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading”, Journal of Computational Chemistry, vol. 31, no. 2, pp. 455–461, Jun. 2009, doi: 10.1002/jcc.21334.
[22] Daina, O. Michielin, and V. Zoete, “SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules”, Scientific Reports, vol. 7, no. 1, Mar. 2017, doi: 10.1038/srep42717.
[23] Cereto-Massagué, M. J. Ojeda, C. Valls, M. Mulero, S. Garcia-Vallvé, and G. Pujadas, “Molecular fingerprint similarity search in virtual screening”, Methods, vol. 71, pp. 58–63, Aug. 2014, doi: 10.1016/j.ymeth.2014.08.005.
[24] Kuwahara and X. Gao, “Analysis of the effects of related fingerprints on molecular similarity using an eigenvalue entropy approach”, Journal of Cheminformatics, vol. 13, no. 1, Mar. 2021, doi: 10.1186/s13321-021-00506-2.
[25] Landrum, The RDKit Documentation The RDKit 2019.09.1 documentation. (n.d.), RDKit. September 1, 2019. [Online]. Available: https://www.rdkit.org/docs/index.html [Accessed August 27, 2024].
[26] Rainio, J. Teuho, and R. Klén, “Evaluation metrics and statistical tests for machine learning”, Scientific Reports, vol. 14, no. 1, Mar. 2024, doi: 10.1038/s41598-024-56706-x.
[27] Chushak and R. A. Clewell, “An integrated approach to predict activators of NRF2 - the transcription factor for oxidative stress response”, Artificial Intelligence in the Life Sciences, vol. 5, p. 100097, Apr. 2024, doi: 10.1016/j.ailsci.2024.100097.
[28] Bajusz, A. Rácz, and K. Héberger, “Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations?”, Journal of Cheminformatics, vol. 7, no. 1, May 2015, doi: 10.1186/s13321-015-0069-3.
[29] Li et al., “Discovery of Keap1−Nrf2 small−molecule inhibitors from phytochemicals based on molecular docking”, Food and Chemical Toxicology, vol. 133, p. 110758, Nov. 2019, doi: 10.1016/j.fct.2019.110758.
[30] A. Alzain et al., “Modulation of NRF2/KEAP1-Mediated Oxidative Stress for cancer treatment by natural products using Pharmacophore-Based screening, molecular docking, and molecular Dynamics studies”, Molecules, vol. 28, no. 16, p. 6003, Aug. 2023, doi: 10.3390/molecules28166003.
[31] Hasanain Abdulhameed Odhar, “Molecular docking analysis and dynamics simulation of salbutamol with the monoamine oxidase B (MAO-B) enzyme”, Bioinformation, 18, no. 3, pp. 304–309, Mar. 2022, doi: https://doi.org/10.6026/97320630018304.
[32] Magesh, Y. Chen, and L. Hu, “Small molecule modulators of KEAP1‐NRF2‐ARE pathway as potential preventive and therapeutic agents”, Medicinal Research Reviews, vol. 32, no. 4, pp. 687–726, May 2012, doi: 10.1002/med.21257.
[33] -S. Keum and B. Choi, “Molecular and chemical regulation of the KEAP1-NRF2 signaling pathway”, Molecules, vol. 19, no. 7, pp. 10074–10089, Jul. 2014, doi: 10.3390/molecules190710074.
[34] Begnini et al., “Importance of binding site hydration and flexibility revealed when optimizing a macrocyclic inhibitor of the KEAP1–NRF2 Protein–Protein interaction”, Journal of Medicinal Chemistry, vol. 65, no. 4, pp. 3473–3517, Feb. 2022, doi: 10.1021/acs.jmedchem.1c01975.
[35] Han et al., “Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway”, Free Radical Biology and Medicine, vol. 113, pp. 59–70, Dec. 2017, doi: 10.1016/j.freeradbiomed.2017.09.014.
[36] Sahu et al., “LC-MS characterized methanolic extract of zanthoxylum armatum possess anti-breast cancer activity through Nrf2-Keap1 pathway: An in-silico, in-vitro and in-vivo evaluation”, Journal of Ethnopharmacology, vol. 269, p. 113758, Dec. 2020, doi: 10.1016/j.jep.2020.113758.
[37] Guan, C. Bian, and Z. Ma, “In vitro and in silico perspectives on the activation of antioxidant responsive element by citrus-derived flavonoids”, Frontiers in Nutrition, vol. 10, Aug. 2023, doi: 10.3389/fnut.2023.1257172.
[38] -R. Li et al., “Discovery of natural flavonoids as activators of Nrf2-mediated defense system: Structure-activity relationship and inhibition of intracellular oxidative insults”, Bioorganic & Medicinal Chemistry, vol. 26, no. 18, pp. 5140–5150, Oct. 2018, doi: 10.1016/j.bmc.2018.09.010.
[39] Kumar, I.-S. Kim, S. V. More, B.-W. Kim, and D.-K. Choi, “Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases”, Natural Product Reports, vol. 31, no. 1, pp. 109–139, Nov. 2013, doi: 10.1039/c3np70065h.
[40] Zhou, Y. Wang, Q. You, and Z. Jiang, “Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present)”, Expert Opinion on Therapeutic Patents, vol. 30, no. 3, pp. 209–225, Feb. 2020, doi: 10.1080/13543776.2020.1715365.
[41] Wu et al., “Discovery of New Triterpenoids Extracted from Camellia oleifera Seed Cake and the Molecular Mechanism Underlying Their Antitumor Activity”, Antioxidants, vol. 12, no. 1, p. 7, Dec. 2022, doi: 10.3390/antiox12010007.
[42] Talebi, M. Talebi, T. Farkhondeh, G. Mishra, S. İlgün, and S. Samarghandian, “New insights into the role of the Nrf2 signaling pathway in green tea catechin applications”, Phytotherapy Research, vol. 35, no. 6, pp. 3078–3112, Feb. 2021, doi: 10.1002/ptr.7033.
[43] Ko, L. D. Wahyudi, Y.-S. Kwon, J.-H. Kim, and H. Yang, “Nuclear Factor Erythroid 2-Related Factor 2 Activating Triterpenoid Saponins from Camellia japonica Roots”, Journal of Natural Products, vol. 81, no. 11, pp. 2399–2409, Nov. 2018, doi: 10.1021/acs.jnatprod.8b00374.
[44] A. Mills, M. A. Ogrodnik, A. Plave, and Y. Mao-Draayer, “Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis”, Frontiers in Neurology, vol. 9, Jan. 2018, doi: 10.3389/fneur.2018.00005.
[45] R. Lynch et al., “Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia”, Annals of Clinical and Translational Neurology, vol. 6, no. 1, pp. 15–26, Nov. 2018, doi: 10.1002/acn3.660.
[46] C. Egbujor, B. Buttari, E. Profumo, P. Telkoparan-Akillilar, and L. Saso, “An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects”, International Journal of Molecular Sciences, vol. 23, no. 15, p. 8466, Jul. 2022, doi: 10.3390/ijms23158466.
[47] Sandhu, Ivraj Singh, et al. “Sustained NRF2 Activation in Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and in Hereditary Tyrosinemia Type 1 (HT1)”, Biochemical Society Transactions, 43, no. 4, Aug. 2015, pp. 650–56. https://doi.org/10.1042/bst20150041.
[48] Taguchi, Keiko, and Masayuki Yamamoto. “The KEAP1–NRF2 System in Cancer”, Frontiers in Oncology, vol. 7, May 2017, https://doi.org/10.3389/fonc.2017.00085.
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Published
Nov 30, 2024
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Nguyễn Minh Quân, Đoàn Nguyễn Việt Hà, Nguyễn Bùi Quốc Huy, Giang Thị Kim Liên, Lê Nguyễn Thiên Hân, and Nguyễn Minh Hiền. “Unveiling the Flavonoid and Theaflavin Compounds from the Genus Camellia in Vietnam towards Inhibiting Keap1-Nrf2 by in Silico Screening Method”. The University of Danang - Journal of Science and Technology, vol. 22, no. 11A, Nov. 2024, pp. 43-52, https://jst-ud.vn/jst-ud/article/view/9421.
