In silico approach of bioactive molecule chitosan 501.1 kDa from snail shell as antioxidant and inhibitor of the keap1-nrf2 protein-protein interaction
DOI:
https://doi.org/10.46542/pe.2023.234.510Keywords:
Antioxidant, Chitosan 501.1 kDa, High-fat diet, KEAP1-NRF2, Oxidative stressAbstract
Background: ROS are created when high levels of oxidative stress occur due to hypercholesterolemia. Nuclear Factor Erythroid 2-related factor (NRF2) controls the expression of antioxidant genes. Kelch-like ECH-associated protein 1 (KEAP1) therapy degrades NRF2. Chitosan 501.1 kDa from snail shells contains bioactive chemicals that can induce NRF2 activity.
Objective: To evaluate the potential antioxidant activity of the bioactive compound in Mw 501.1 kDa chitosan by targeting KEAP1 and NRF2 proteins in-silico.
Method: The 3D structures of the bioactive compounds chitosan and control 51M were derived from the PubChem database, and the proteins were derived from the RCSB PDB. The biological activity of chitosan bioactive compounds was predicted using the PASS Online server. Molecular docking was performed using Hex 8.0.0 Cuda with Shape+Electro+DARS and visualised with Discovery Studio. The biological activity of chitosan compounds was predicted as lipotropic and antioxidant.
Result: The discovery of the bioactive compound chitosan 501.1 kDa interacted strongly with KEAP1. The bioactive compound chitosan also inhibited KEAP1 through residues GLN75 and LEU84 at the 51M-KEAP1 interaction.
Conclusion: The bioactive compound chitosan 501.1 kDa could inhibit the interaction of KEAP1-NRF2 proteins so that NRF2 could transcribe antioxidant genes. Therefore, may serve as a suitable alternative.
References
Ahtikoski, A.M., Kangas, J., Salonen, R., Puistola, U. & Karihtala, P. (2019). Cytoplasmic Keap1 expression is associated with poor prognosis in endometrial cancer. Anticancer Research, 39(2):585–590 https://doi.org/10.21873/anticanres.13151
Avelelas, F., Horta, A., Pinto, L.F.V., Marques, S.C., Nunes, P.M., Pedrosa, R. & Leandro, S.M. (2019). Antifungal and antioxidant properties of chitosan polymers obtained from nontraditional Polybius henslowii sources. Marine Drugs, 17(4):1–15 https://doi.org/10.3390/md17040239
Ayunda, R.D., Prasetyastuti, P & Hastuti, P. (2019). Effect of 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chroman-4-one on level of mangan-superoxide dismutase (mn-sod) and superoxide dismutase 2 (SOD2) gene expression in hyperlipidemia rats. Indonesian Journal of Pharmacy, 30(3):180–186 https://doi.org/10.14499/indonesianjpharm30iss3pp178
Bhat, A.H., Bhat, I.U.H., Khalil, H.P.S.A., Mishra, R.K., Datt, M. & Banthia, A.K. (2011). Development and material properties of chitosan and phosphomolybdic acid-based composites. Journal of Composite Materials, 45(1):39–49 https://doi.org/10.1177/0021998310371552
Biswas, S., Das, R. & Banerjee, E.R. (2017). Role of free radicals in human inflammatory diseases. AIMS Biophysics, 4(4):596–614 https://doi.org/10.3934/biophy.2017.4.596
Chang, S.H., Wu, C.H. & Tsai, G.J. (2018). Effects of chitosan molecular weight on its antioxidant and antimutagenic properties. Carbohydrate Polymers, 181:1026–1032 https://doi.org/10.1016/j.carbpol.2017.11.047
Chen, B., Yanrong, L., Younan, C. & Jingqiu, C. (2023). The role of Nrf2 in oxidative stress-induced endothelial injuries. Bioscientific, 3(224):83-99 https://doi.org/10.1530/JOE-14-0662
Chtourou, Y., Slima, A.B., Makni, M., Gdoura, R. & Fetoui, H. (2015). Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats. Pharmacological reports, 67(6):1090-1097 https://doi.org/10.1016/j.pharep.2015.04.002
Cocuzza, M., Sikka, S.C., Athayde, K.S. & Agarwal, A. (2007). Clinical relevance of oxidative stress and sperm chromatin damage in male infertility: An eevidence-based analysis. International Braz J Urology, 33(5):603–621 https://doi.org/10.1590/S1677-55382007000500002
Csonka, C., Sárközy, M., Pipicz, M., Dux, L. & Csont, T. (2016). Modulation of Hypercholesterolemia-Induced Oxidative/Nitrative Stress in the Heart. Oxidative Medicine and Cellular Longevity. 3863726 https://doi.org/10.1155/2016/3863726
Debbabi, F., Gargoubi, S., Hadj Ayed, M.A. & Abdessalem, S. Ben. (2017). Development and characterization of antibacterial braided polyamide suture coated with chitosan-citric acid biopolymer. Journal of Biomaterials Applications, 32(3):384–398 https://doi.org/10.1177/0885328217721868
Filimonov, D.A., Lagunin, A.A., Gloriozova, T.A., Rudik A.V., Druzhilovskii D.S., Pogodin P.V. & Poroikov V.V. (2014). Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chemistry of Heterocyclic Compounds, 50(3):444-457
Kansanen, E., Kuosmanen, S.M., Leinonen, H. & Levonen, A.L. (2013). The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol. 1:45-49 https://doi.org/10.1016/j.redox.2012.10.001
Kim, T.H., Jin, H., Kim, H.W., Cho, M.H. & Cho, C.S. (2006). Mannosylated chitosan nanoparticle-based cytokine gene therapy suppressed cancer growth in BALB/c mice bearing CT-26 carcinoma cells. Molecular Cancer Therapeutics, 5(7):1723–1732 https://doi.org/10.1158/1535-7163.MCT-05-0540
Leung, C.H., Zhang, J.T., Yang, G.J., Liu, H., Han, Q.B. & Ma, D.L. (2019). Emerging screening approaches in the development of Nrf2-keap1 protein-protein interaction inhibitors. International Journal of Molecular Sciences, 20(18) https://doi.org/10.3390/ijms20184445
Li, J., Han, A., Zhang, L., Meng, Y., Xu, L., Ma, F. & Liu, R. (2022). Chitosan oligosaccharide alleviates the growth inhibition caused by physcion and synergistically enhances resilience in maize seedlings. Scientific Reports, 12(1):1–12 https://doi.org/10.1038/s41598-021-04153-3
Li, M., Huang, W., Jie, F., Wang, M., Zhong, Y., Chen, Q., & Lu, B. (2019). Discovery of Keap1−Nrf2 small−molecule inhibitors from phytochemicals based on molecular docking. Food and Chemical Toxicology, 133:110758 https://doi.org/10.1016/j.fct.2019.110758
Liping, L., Kexin, L., Huipu, D., Jia, L. & Jie, Z. (2020). Study on Preparation of a Chitosan/Vitamin C Complex and Its Properties in Cosmetics. Natural Product Communications, 15(10) https://doi.org/10.1177/1934578X20946876
Marianti, A. & Mahatmanti, F.W. (2018). Synergetic effect of chitosan and vitamin C on the oxidative enzyme status in rats exposed to lead acetate. Acta Scientiarum - Biological Sciences, 40(1):1–8 https://doi.org/10.4025/actascibiolsci.v40i1.41869
Meng, N., Tang, H., Zhang, H., Jiang, C., Su, L., Min, X., Zhang, W., Zhang, H., Miao, Z., Zhang, W. & Zhuang, C. (2018). Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis. Free Radical Biology and Medicine, 117:228–237 https://doi.org/10.1016/j.freeradbiomed.2018.02.010
Niedzielska, E., Smaga, I., Gawlik, M., Moniczewski, A., Stankowicz, P., Pera, J. & Filip, M. (2016). Oxidative Stress in Neurodegenerative Diseases. Molecular Neurobiology, 53(6):4094–4125 https://doi.org/10.1007/s12035-015-9337-5
Niki, E. (2012). Do antioxidants impair signalling by reactive oxygen species and lipid oxidation products? FEBS Letters, 586(21):3767–3770 https://doi.org/10.1016/j.febslet.2012.09.025
Rizzo, M., Giglio, R.V., Nikolic, D., Patti, A.M., Campanella, C., Cocchi, M., Katsiki, N. & Montalto, G. (2014). Effects of chitosan on plasma lipids and lipoproteins: A 4-month prospective pilot study. Angiology, 65(6):538–542 https://doi.org/10.1177/0003319713493126
Tanji, K., Maruyama, A., Odagiri, S., Mori, F., Itoh, K., Kakita, A., Takahashi, H. & Wakabayashi, K. (2013). Keap1 is localised in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. Journal of Neuropathology and Experimental Neurology, 72(1):18-28 https://doi.org/10.1097/NEN.0b013e31827b5713
Umar, U., Surahmaida, S., Alta, R. & Ningrum, R.S. (2019). Characterization of Chitosan from Shell of Snail (Achatina Fulica F) and Its Antibacterial Activity against Staphylococcus aureus. Biota, 12(1) https://doi.org/10.20414/jb.v12i1.180
Umarudin., Widyarti, S., Warsito. & Rahayu, S. (2022). Effect of Lissachatina fulica chitosan on the antioxidant and lipid profile of hypercholesterolemic male Wistar rats. J Pharm Pharmacogn Res, 10(6):995–1005 https://doi.org/10.56499/jppres22.1468_10.6.995
Wells, G. (2015). Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction. Biochemical Society Transactions, 43 https://doi.org/10.1042/BST20150051
Zhuang, C., Wu, Z., Xing, C. & Miao, Z. (2017). Small molecules inhibiting Keap1-Nrf2 protein-protein interactions: a novel approach to activate Nrf2 function. MedChemComm, 8(2):286–294 https://doi.org/10.1039/c6md00500d
