Computational study of the main flavonoids from Chrysobalanus icaco L. against NADPH-oxidase and in vitro Antioxidant Activity

Authors

DOI:

https://doi.org/10.33448/rsd-v11i6.28542

Keywords:

Chrysobalanus icaco; Flavonoids; Antioxidant activity; In silico study.

Abstract

The generation of free radicals is a physiological event resulting mainly from the cellular respiration process and the overactivation of the NOX leads to an excess production of ROS that is associated with oxidative stress. Chrysobalanus icaco, a medicinal plant that belongs to the Chrysobalanaceae family, possesses a high number of polyphenols, including phenolic acids and flavonoids. Due to its phytochemical composition, this study aimed to evaluate the antioxidant potential of the hydroalcoholic extract from the leaves of Chrysobalanus icaco (HECi) and the inhibitory potential of its main flavonoids against NOX. The in silico predictions of absorption, distribution, metabolism, excretion, and toxicity (ADMET), drug-likeness properties, and molecular docking with the enzyme NOX (PDB code 2CDU) were also performed to support the experimental results. The phytochemical screening of the HECi showed the presence of phenols and flavonoids. HECi performed an excellent antioxidant activity (IC50 = 8.1 μg/mL), probably due to its rich phenolic (220.11 ± 0.4 mg GAE/g) and flavonoid (110.98 ± 0.37 mg QE/g) constitution. The ADMET prediction indicated that myricetin and quercetin had the best pharmacokinetic parameters. The molecular docking results showed that myricetin and especially quercetin had strong docking score on NOX (ΔG = –8.1 kcal/mol and ΔG = –8.3 kcal/mol, respectively). Frontier Orbital’s analyzes (HOMO and LUMO) suggested that quercetin has better antioxidant properties than myricetin. Our results demonstrate for the first time the in silico action of quercetin against NOX, as well as reiterate the antioxidant potential of C. icaco.

References

Agati, G., Brunetti, C., Fini, A., Gori, A., Guidi, L., Landi, M., Sebastiani, F., & Tattini, M. (2020). Are Flavonoids Effective Antioxidants in Plants? Twenty Years of Our Investigation. Antioxidants, 9(11), 1098. https://doi.org/10.3390/antiox9111098.

Al-Nour, M. Y., Ibrahim, M. M., & Elsaman, T. (2019). Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action. Current Pharmacology Reports, 5(4), 255–280. https://doi.org/10.1007/s40495-019-00181-w.

Araújo-Filho, H. G., Dias, J. D. S., Quintans-Júnior, L. J., Santos, M. R. V., White, P. A. S., Barreto, R. S. S., Barreto, A. S., Estevam, C. S., Araujo, S. S., Almeida, J. R. G. S., Menezes, I. R. A., Coutinho, H. D. M., & Quintans, J. S. S. (2016). Phytochemical screening and analgesic profile of the lyophilized aqueous extract obtained from Chrysobalanus icaco leaves in experimental protocols. Pharmaceutical Biology, 54(12), 3055–3062. https://doi.org/10.1080/13880209.2016.1204618.

Arce, A., Marchiaro, A., Rodríguez, O., & Soto, A. (2006). Essential oil terpenless by extraction using organic solvents or ionic liquids. AIChE Journal, 52(6), 2089–2097. https://doi.org/10.1002/aic.10844.

Arfin, S., Jha, N. K., Jha, S. K., Kesari, K. K., Ruokolainen, J., Roychoudhury, S., Rathi, B., & Kumar, D. (2021). Oxidative Stress in Cancer Cell Metabolism. Antioxidants, 10(5), 642. https://doi.org/10.3390/antiox10050642.

Bang, S.-H., Hyun, Y.-J., Shim, J., Hong, S.-W., & Kim, D.-H. (2015). Metabolism of Rutin and Poncirin by Human Intestinal Microbiota and Cloning of Their Metabolizing α-L-Rhamnosidase from Bifidobacterium dentium. Journal of Microbiology and Biotechnology, 25(1), 18–25. https://doi.org/10.4014/jmb.1404.04060.

Barbosa, A. P. de O., Silveira, G. de O., de Menezes, I. A. C., Rezende Neto, J. M., Bitencurt, J. L. C., Estavam, C. dos S., de Lima, A. do C. B., Thomazzi, S. M., Guimarães, A. G., Quintans-Junior, L. J., & dos Santos, M. R. V. (2013). Antidiabetic Effect of theChrysobalanus icacoL. Aqueous Extract in Rats. Journal of Medicinal Food, 16(6), 538–543. https://doi.org/10.1089/jmf.2012.0084.

Barbosa, W. L. R., Peres, A., Gallori, S., & Vincieri, F. F. (2006). Determination of myricetin derivatives in Chrysobalanus icaco L. (Chrysobalanaceae). Revista Brasileira de Farmacognosia, 16(3), 333–337. https://doi.org/10.1590/s0102-695x2006000300009.

Bedard, K., & Krause, K.-H. (2007). The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiological Reviews, 87(1), 245–313. https://doi.org/10.1152/physrev.00044.2005.

Bickerton, G. R., Paolini, G. V., Besnard, J., Muresan, S., & Hopkins, A. L. (2012). Quantifying the chemical beauty of drugs. Nature Chemistry, 4(2), 90–98. https://doi.org/10.1038/nchem.1243.

Biovia, Dassault Systèmes. (2021). Discovery studio visualizer. San Diego, CA, USA, 936.

Braga, R. P., Moraes, F. K. C., Manhaes, M. M., Andrade, M. A., Baetas, A. C., Almeida, E. D., Fontes, E. A., Silva, M. V. S., Silva, M. N., Arruda, M. S. P., & Borges, R. S. (2011). An Electronic Study of Tocopherol-Ring Regioisomers as Antioxidants. Journal of Computational and Theoretical Nanoscience, 8(10), 2061–2065. https://doi.org/10.1166/jctn.2011.1926.

Castilho, R. O., de Oliveira, R. R., & Kaplan, M. A. C. (2005). Licanolide, a new triterpene lactone from Licania tomentosa. Fitoterapia, 76(6), 562–566. https://doi.org/10.1016/j.fitote.2005.04.018.

Castilho, R. O., & Kaplan, M. A. C. (2011). Phytochemical study and antimicrobial activity of Chrysobalanus icaco. Chemistry of Natural Compounds, 47(3), 436–437. https://doi.org/10.1007/s10600-011-9953-x.

Chaudhuri, S., Badisa, R. B., Pilarinou, E., & Walker, E. (2002). Licamichauxiioic-A and -B Acids - TwoEnt-Kaurene Diterpenoids fromLicania Michauxii. Natural Product Letters, 16(1), 39–45. https://doi.org/10.1080/1057563029001/4836.

Chocry, M., & Leloup, L. (2020). The NADPH Oxidase Family and Its Inhibitors. Antioxidants & Redox Signaling, 33(5), 332–353. https://doi.org/10.1089/ars.2019.7915.

Devadasu, V. R., Deb, P. K., Maheshwari, R., Sharma, P., & Tekade, R. K. (2018). Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs. Dosage Form Design Considerations, 149–178. https://doi.org/10.1016/b978-0-12-814423-7.00005-8.

Farouk, A., Mohsen, M., Ali, H., Shaaban, H., & Albaridi, N. (2021). Antioxidant Activity and Molecular Docking Study of Volatile Constituents from Different Aromatic Lamiaceous Plants Cultivated in Madinah Monawara, Saudi Arabia. Molecules, 26(14), 4145. https://doi.org/10.3390/molecules26144145.

Feitosa, E. A., Xavier, H. S., & Randau, K. P. (2012). Chrysobalanaceae: traditional uses, phytochemistry and pharmacology. Revista Brasileira de Farmacognosia, 22(5), 1181–1186. https://doi.org/10.1590/s0102-695x2012005000080.

Felhi, S., Baccouch, N., Ben Salah, H., Smaoui, S., Allouche, N., Gharsallah, N., & Kadri, A. (2016). Nutritional constituents, phytochemical profiles, in vitro antioxidant and antimicrobial properties, and gas chromatography–mass spectrometry analysis of various solvent extracts from grape seeds (Vitis vinifera L.). Food Science and Biotechnology, 25(6), 1537–1544. https://doi.org/10.1007/s10068-016-0238-9.

Fernandes, J., Castilho, R. O., da Costa, M. R., Wagner-Souza, K., Coelho Kaplan, M. A., & Gattass, C. R. (2003). Pentacyclic triterpenes from Chrysobalanaceae species: cytotoxicity on multidrug resistant and sensitive leukemia cell lines. Cancer Letters, 190(2), 165–169. https://doi.org/10.1016/s0304-3835(02)00593-1.

Ganesan, K., & Xu, B. (2017). A Critical Review on Polyphenols and Health Benefits of Black Soybeans. Nutrients, 9(5), 455. https://doi.org/10.3390/nu9050455.

Hano, C., & Tungmunnithum, D. (2020). Plant Polyphenols, More than Just Simple Natural Antioxidants: Oxidative Stress, Aging and Age-Related Diseases. Medicines, 7(5), 26. https://doi.org/10.3390/medicines7050026.

Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4(1). https://doi.org/10.1186/1758-2946-4-17.

Herrera-Calderon, O., Chacaltana-Ramos, L. J., Huayanca-Gutiérrez, I. C., Algarni, M. A., Alqarni, M., & Batiha, G. E.-S. (2021). Chemical Constituents, In Vitro Antioxidant Activity and In Silico Study on NADPH Oxidase of Allium sativum L. (Garlic) Essential Oil. Antioxidants, 10(11), 1844. https://doi.org/10.3390/antiox10111844.

Hevener, K. E., Zhao, W., Ball, D. M., Babaoglu, K., Qi, J., White, S. W., & Lee, R. E. (2009). Validation of Molecular Docking Programs for Virtual Screening against Dihydropteroate Synthase. Journal of Chemical Information and Modeling, 49(2), 444–460. https://doi.org/10.1021/ci800293n.

Hritcu, L., Ionita, R., Postu, P. A., Gupta, G. K., Turkez, H., Lima, T. C., Carvalho, C. U. S., & de Sousa, D. P. (2017). Antidepressant Flavonoids and Their Relationship with Oxidative Stress. Oxidative Medicine and Cellular Longevity, 2017, 1–18. https://doi.org/10.1155/2017/5762172.

Izzo, C., Vitillo, P., Di Pietro, P., Visco, V., Strianese, A., Virtuoso, N., Ciccarelli, M., Galasso, G., Carrizzo, A., & Vecchione, C. (2021). The Role of Oxidative Stress in Cardiovascular Aging and Cardiovascular Diseases. Life, 11(1), 60. https://doi.org/10.3390/life11010060.

Joshi, S., & Khan, S. R. (2019). NADPH oxidase: a therapeutic target for hyperoxaluria-induced oxidative stress – an update. Future Medicinal Chemistry, 11(23), 2975–2978. https://doi.org/10.4155/fmc-2019-0275.

Khlebnikov, A. I., Schepetkin, I. A., Domina, N. G., Kirpotina, L. N., & Quinn, M. T. (2007). Improved quantitative structure–activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems. Bioorganic & Medicinal Chemistry, 15(4), 1749–1770. https://doi.org/10.1016/j.bmc.2006.11.037.

Krishnaiah, D., Sarbatly, R., & Nithyanandam, R. (2011). A review of the antioxidant potential of medicinal plant species. Food and Bioproducts Processing, 89(3), 217–233. https://doi.org/10.1016/j.fbp.2010.04.008.

Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., Gargiulo, G., Testa, G., Cacciatore, F., Bonaduce, D., & Abete, P. (2018). Oxidative stress, aging, and diseases. Clinical Interventions in Aging, Volume 13, 757–772. https://doi.org/10.2147/cia.s158513.

Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337–341. https://doi.org/10.1016/j.ddtec.2004.11.007.

Lountos, G. T., Jiang, R., Wellborn, W. B., Thaler, T. L., Bommarius, A. S., & Orville, A. M. (2006). The Crystal Structure of NAD(P)H Oxidase from Lactobacillus sanfranciscensis: Insights into the Conversion of O2 into Two Water Molecules by the Flavoenzyme,. Biochemistry, 45(32), 9648–9659. https://doi.org/10.1021/bi060692p.

Luo, M., Tian, R., Yang, Z., Peng, Y.-Y., & Lu, N. (2019). Quercetin suppressed NADPH oxidase-derived oxidative stress via heme oxygenase-1 induction in macrophages. Archives of Biochemistry and Biophysics, 671, 69–76. https://doi.org/10.1016/j.abb.2019.06.007.

Mammen, D., & Daniel, M. (2012). A critical evaluation on the reliability of two aluminum chloride chelation methods for quantification of flavonoids. Food Chemistry, 135(3), 1365–1368. https://doi.org/10.1016/j.foodchem.2012.05.109.

McCann, S., & Roulston, C. (2013). NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives. Brain Sciences, 3(4), 561–598. https://doi.org/10.3390/brainsci3020561.

Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry, 19(14), 1639–1662. https://doi.org/10.1002/(sici)1096-987x(19981115)19:14<1639::aid-jcc10>3.0.co;2-b.

Oda, F. B. (2014). Avaliação da utilização de subprodutos de Coffea arabica L. para fins cosméticos (p. 52) [Undergraduate Dissertation].

Oliveira, M., Eloir Paulo Schenkel, & Palazzo, C. (2017). Farmacognosia do produto natural ao medicamento. Porto Alegre, Rs Artmed.

Onilude, H. A., Kazeem, M. I., & Adu, O. B. (2021). Chrysobalanus icaco: A review of its phytochemistry and pharmacology. Journal of Integrative Medicine, 19(1), 13–19. https://doi.org/10.1016/j.joim.2020.10.001.

Pandey, K. B., & Rizvi, S. I. (2009). Plant Polyphenols as Dietary Antioxidants in Human Health and Disease. Oxidative Medicine and Cellular Longevity, 2(5), 270–278. https://doi.org/10.4161/oxim.2.5.9498.

Pires, D., Blundell, T., & Ascher, D. (2015). pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. ACS Publications. https://dx.doi.org/10.1021%2Facs.jmedchem.5b00104.

Qin, L., Wang, W., You, S., Dong, J., Zhou, Y., & Wang, J. (2014). In vitro antioxidant activity and in vivo antifatigue effect of layered double hydroxide nanoparticles as delivery vehicles for folic acid. International Journal of Nanomedicine, 9, 5701. https://doi.org/10.2147/ijn.s74306.

Rahmani, H., Ghavamipour, F., & Sajedi, R. H. (2019). Bioluminescence Detection of Superoxide Anion Using Aequorin. Analytical Chemistry, 91(20), 12768–12774. https://doi.org/10.1021/acs.analchem.9b02293.

Ramos, L. V. R., Barros, A. S. M., & Dolabela, M. F. (2020). Análise in silico de metabólitos ativos isolados de Libidibia ferrea Martius. Research, Society and Development, 9(12), e7991210910. https://doi.org/10.33448/rsd-v9i12.10910.

Riva, A., Kolimár, D., Spittler, A., Wisgrill, L., Herbold, C. W., Abrankó, L., & Berry, D. (2020). Conversion of Rutin, a Prevalent Dietary Flavonol, by the Human Gut Microbiota. Frontiers in Microbiology, 11. https://doi.org/10.3389/fmicb.2020.585428.

Roy, J., Galano, J., Durand, T., Le Guennec, J., & Chung‐Yung Lee, J. (2017). Physiological role of reactive oxygen species as promoters of natural defenses. The FASEB Journal, 31(9), 3729–3745. https://doi.org/10.1096/fj.201700170r.

Salamanca Viloria, J., Allega, M. F., Lambrughi, M., & Papaleo, E. (2017). An optimal distance cutoff for contact-based Protein Structure Networks using side-chain centers of mass. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-01498-6.

Sánchez, M., Galisteo, M., Vera, R., Villar, I. C., Zarzuelo, A., Tamargo, J., Pérez-Vizcaíno, F., & Duarte, J. (2006). Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. Journal of Hypertension, 24(1), 75–84. https://doi.org/10.1097/01.hjh.0000198029.22472.d9.

Schrödinger, L., & DeLano, W. (2020). PyMOL | www.pymol.org. Www.pymol.org. http://www.pymol.org/pymol.

Sherman, W., Beard, H. S., & Farid, R. (2006). Use of an Induced Fit Receptor Structure in Virtual Screening. Chemical Biology Drug Design, 67(1), 83–84. https://doi.org/10.1111/j.1747-0285.2005.00327.x.

Silva, J. B., Peres, A. R. N., Paixão, T., Silva, A. B., Baetas, A., Barbosa, W. R., Monteiro, M. & Andrade, M.(2017). Antifungal activity of hydroalcoholic extract of Chrysobalanus icaco against oral clinical isolates of Candida Species. Pharmacognosy Research, 9(1), 96. https://doi.org/10.4103/0974-8490.199772.

Simone Badal Mccreath, & Rupika Delgoda. (2016). Pharmacognosy : fundamentals, applications and strategies. Academic Press.

Singleton, V. L., Orthofer, R., & Lamuela-Raventós, R. M. (1999). [14] Analysis of total phenols and other oxidation substrates and antioxidants by means of folin-ciocalteu reagent. Oxidants and Antioxidants Part A, 299, 152–178. https://doi.org/10.1016/s0076-6879(99)99017-1.

Singleton, V. L., & Rossi, J. A. (1965). Colorimetry of Total Phenolics with Phosphomolybdic-Phosphotungstic Acid Reagents. American Journal of Enology and Viticulture, 16(3), 144–158.

Siramshetty, V. B., Nickel, J., Omieczynski, C., Gohlke, B.-O., Drwal, M. N., & Preissner, R. (2015). WITHDRAWN—a resource for withdrawn and discontinued drugs. Nucleic Acids Research, 44(D1), D1080–D1086. https://doi.org/10.1093/nar/gkv1192.

Susanti, H. (2019). Total phenolic content and antioxidant activities of binahong (Anredera cordifolia.). Jurnal Kedokteran Dan Kesehatan Indonesia, 10(2), 171–175. https://doi.org/10.20885/jkki.vol10.iss2.art9.

Tarafdar, A., & Pula, G. (2018). The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders. International Journal of Molecular Sciences, 19(12), 3824. https://doi.org/10.3390/ijms19123824.

Thilakarathna, S., & Rupasinghe, H. (2013). Flavonoid Bioavailability and Attempts for Bioavailability Enhancement. Nutrients, 5(9), 3367–3387. https://doi.org/10.3390/nu5093367.

Trott, O., & Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), NA-NA. https://doi.org/10.1002/jcc.21334.

Valentová, K., Vrba, J., Bancířová, M., Ulrichová, J., & Křen, V. (2014). Isoquercitrin: Pharmacology, toxicology, and metabolism. Food and Chemical Toxicology, 68, 267–282. https://doi.org/10.1016/j.fct.2014.03.018.

Walle, T., Browning, A. M., Steed, L. L., Reed, S. G., & Walle, U. K. (2005). Flavonoid Glucosides Are Hydrolyzed and Thus Activated in the Oral Cavity in Humans. The Journal of Nutrition, 135(1), 48–52. https://doi.org/10.1093/jn/135.1.48.

Wang, G., Xue, Y., An, L., Zheng, Y., Dou, Y., Zhang, L., & Liu, Y. (2015). Theoretical study on the structural and antioxidant properties of some recently synthesised 2,4,5-trimethoxy chalcones. Food Chemistry, 171, 89–97. https://doi.org/10.1016/j.foodchem.2014.08.106.

Wang, X., Chen, Y., Wang, Q., Sun, L., Li, G., Zhang, C., Huang, J., Chen, L., & Zhai, H. (2017). Support for Natural Small-Molecule Phenols as Anxiolytics. Molecules, 22(12), 2138. https://doi.org/10.3390/molecules22122138.

Wen, K., Fang, X., Yang, J., Yao, Y., Nandakumar, K. S., Salem, M. L., & Cheng, K. (2021). Recent Research on Flavonoids and their Biomedical Applications. Current Medicinal Chemistry, 28(5), 1042–1066. https://doi.org/10.2174/0929867327666200713184138.

Williams, R. J., Spencer, J. P. E., & Rice-Evans, C. (2004). Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine, 36(7), 838–849. https://doi.org/10.1016/j.freeradbiomed.2004.01.001.

Xiao, J. (2015). Dietary Flavonoid Aglycones and Their Glycosides: Which Show Better Biological Significance? Critical Reviews in Food Science and Nutrition. https://doi.org/10.1080/10408398.2015.1032400.

Xiao, J., & Hogger, P. (2013). Metabolism of Dietary Flavonoids in Liver Microsomes. Current Drug Metabolism, 14(4), 381–391. https://doi.org/10.2174/1389200211314040003.

Xue, Y., Zheng, Y., An, L., Dou, Y., & Liu, Y. (2014). Density functional theory study of the structure–antioxidant activity of polyphenolic deoxybenzoins. Food Chemistry, 151, 198–206. https://doi.org/10.1016/j.foodchem.2013.11.064.

Yousefian, M., Shakour, N., Hosseinzadeh, H., Hayes, A. W., Hadizadeh, F., & Karimi, G. (2019). The natural phenolic compounds as modulators of NADPH oxidases in hypertension. Phytomedicine, 55, 200–213. https://doi.org/10.1016/j.phymed.2018.08.002.

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19/04/2022

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PANTOJA, L. V. P. da S. .; TRINDADE, S. S. A. .; CARNEIRO, A. da S.; SILVA, J. P. B.; PAIXÃO, T. P. da; ROMEIRO, C. F. R.; MORAES, C. S. P. de; PINTO, A. C. G.; RAPOSO, N. R. B. .; ANDRADE, M. A. de. Computational study of the main flavonoids from Chrysobalanus icaco L. against NADPH-oxidase and in vitro Antioxidant Activity. Research, Society and Development, [S. l.], v. 11, n. 6, p. e5011628542, 2022. DOI: 10.33448/rsd-v11i6.28542. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/28542. Acesso em: 22 may. 2022.

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Agrarian and Biological Sciences