Flavonoid Compounds of Buah Merah (Pandanus conoideus Lamk) as a Potent Oxidative Stress Modulator in ROS-induced Cancer: In Silico Approach


Abd. Kakhar Umar(1*), Faruk Jayanto Kelutur(2), James H. Zothantluanga(3)

(1) Department of Pharmacy, Faculty of Math and Natural Sciences, Universitas Tadulako, Palu 94148
(2) Department of Chemistry, Faculty of Math and Natural Sciences, Universitas Pattimura, Ambon 97233
(3) Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh 786004, Assam
(*) Corresponding Author


Buah Merah, a typical fruit from Papua, Indonesia which is used empirically in cancer therapy is rich in carotenoids and flavonoids. However, the mechanisms by which Buah Merah ameliorates cancer remained unknown. Natural antioxidant enzymes and pro-oxidant enzymes modulation significantly suppressed ROS production and cancer growth. Therefore, the determination of target enzymes of Buah Merah contents was studied through an in silico approach. Carotenoid and flavonoid compounds from Buah Merah were docked to 7 ROS modulating enzymes using Autodock Vina and the interaction stability was studied using the CABS Flex 2.0 server. The crucial amino acids of each enzyme were determined using DockFlin and prediction of acute oral toxicity of each test ligand was studied using ProTox-II. Based on the molecular docking results, quercetin 3'-glucoside is the most potent compound in binding to CAT, GR, GPx, SOD, LOX, and NOX with binding energy values of -11.2, -9.7, -8.6, -10.2, -10.7, and -12.8 kcal/mol, respectively. Meanwhile, taxifolin 3-O-α-arabinopyranose produced the highest binding affinity of -10.0 kcal/mol at the XO. Each test ligand formed stable interactions with ROS modulating enzymes and formed bonds with crucial amino acids resulting in strong adhesion compared to native and reference ligands. The glucoside group of quercetin 3'-glucoside plays an essential role in determining the proper position in the attachment and supports the formation of hydrogen bonds with receptors. With low acute oral toxicity, it can be concluded that quercetin 3'-glucoside from Buah Merah is a potent oxidative stress modulator in cancer prevention and therapy.


ROS-induced cancer; Buah Merah; Pandanus conoideus Lamk; Quercetin 3’-glucoside; In silico

Full Text:



Abotaleb, M., Samuel, S., Varghese, E., Varghese, S., Kubatka, P., Liskova, A. and Büsselberg, D. (2018) ‘Flavonoids in Cancer and Apoptosis’, Cancers, 11(1), p. 28. doi: 10.3390/cancers11010028.

Arora, S., Lohiya, G., Moharir, K., Shah, S. and Yende, S. (2020) ‘Identification of Potential Flavonoid Inhibitors of the SARS-CoV-2 Main Protease 6YNQ: A Molecular Docking Study’, Digital Chinese Medicine, 3(4), pp. 239–248. doi: 10.1016/j.dcmed.2020.12.003.

Bauer, G. (2012) ‘Tumor cell-protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling’, Anticancer Research, 32(7), pp. 2599–2624.

Bishayee, K. and Khuda-Bukhsh, A. R. (2013) ‘5-Lipoxygenase Antagonist therapy: a new approach towards targeted cancer chemotherapy’, Acta Biochimica et Biophysica Sinica, 45(9), pp. 709–719. doi: 10.1093/abbs/gmt064.

Chen, B., Shen, Z., Wu, D., Xie, X., Xu, X., Lv, L., Dai, H., Chen, J. and Gan, X. (2019) ‘Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway’, BioMed Research International, 2019, pp. 1–12. doi: 10.1155/2019/7640547.

Chirumbolo, S., Bjørklund, G., Lysiuk, R., Vella, A., Lenchyk, L. and Upyr, T. (2018) ‘Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways’, International Journal of Molecular Sciences, 19(11), p. 3568. doi: 10.3390/ijms19113568.

Colovos, C. and Yeates, T. O. (1993) ‘Verification of protein structures: Patterns of nonbonded atomic interactions’, Protein Science, 2(9), pp. 1511–1519. doi: 10.1002/pro.5560020916.

Gào, X. and Schöttker, B. (2017) ‘Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews’, Oncotarget, 8(31), pp. 51888–51906. doi: 10.18632/oncotarget.17128.

Glorieux, C. and Calderon, P. B. (2018) ‘Catalase down-regulation in cancer cells exposed to arsenic trioxide is involved in their increased sensitivity to a pro-oxidant treatment’, Cancer Cell International, 18(1), p. 24. doi: 10.1186/s12935-018-0524-0.

Goh, J., Enns, L., Fatemie, S., Hopkins, H., Morton, J., Pettan-Brewer, C. and Ladiges, W. (2011) ‘Mitochondrial targeted catalase suppresses invasive breast cancer in mice’, BMC Cancer, 11(1), p. 191. doi: 10.1186/1471-2407-11-191.

Kennedy, L., Sandhu, J. K., Harper, M. E. and Cuperlovic‐culf, M. (2020) ‘Role of glutathione in cancer: From mechanisms to therapies’, Biomolecules, 10(10), pp. 1–27. doi: 10.3390/biom10101429.

Kleywegt, G. J. and Jones, T. A. (1996) ‘Phi/Psi-chology: Ramachandran revisited’, Structure, 4(12), pp. 1395–1400. doi: 10.1016/S0969-2126(96)00147-5.

Kopustinskiene, D. M., Jakstas, V., Savickas, A. and Bernatoniene, J. (2020) ‘Flavonoids as anticancer agents’, Nutrients, 12(2), pp. 1–24. doi: 10.3390/nu12020457.

Kurcinski, M., Oleniecki, T., Ciemny, M. P., Kuriata, A., Kolinski, A. and Kmiecik, S. (2019) ‘CABS-flex standalone: a simulation environment for fast modeling of protein flexibility’, Bioinformatics. Edited by A. Valencia, 35(4), pp. 694–695. doi: 10.1093/bioinformatics/bty685.

Landry, W. D. and Cotter, T. G. (2014) ‘ROS signalling, NADPH oxidases and cancer’, Biochemical Society Transactions, 42(4), pp. 934–938. doi: 10.1042/BST20140060.

Laskowski, R. A., MacArthur, M. W., Moss, D. S. and Thornton, J. M. (1993) ‘PROCHECK: a program to check the stereochemical quality of protein structures’, Journal of Applied Crystallography, 26(2), pp. 283–291. doi: 10.1107/S0021889892009944.

Materska, M. (2008) ‘Quercetin and Its Derivatives : Chemical Structure and Bioactivity -a Review’, Polish journal of food and nutrition sciences, 58(4), pp. 407–413.

Meitzler, J. L., Antony, S., Wu, Y., Juhasz, A., Liu, H., Jiang, G., Lu, J., Roy, K. and Doroshow, J. H. (2014) ‘NADPH Oxidases: A Perspective on Reactive Oxygen Species Production in Tumor Biology’, Antioxidants & Redox Signaling, 20(17), pp. 2873–2889. doi: 10.1089/ars.2013.5603.

Michielin, O. and Zoete, V. (2019) SwissDrugDesign. Available at: http://www.swisstargetprediction.ch/ (Accessed: 26 July 2021).

Muchtaridi, Y. A., Megantara, S. and Purnomo, H. (2018) Kimia Medisinal: Dasar-Dasar dalam Perancangan Obat (Pertama). Jakarta: Prenamedia Group.

Nuringtyas, T. R., Pratama, Y., Galih, G., Wahyuono, S. and Moeljopawiro, S. (2015) ‘Cytotoxicity of Buah Merah (Pandanus conoideus Lamk.) Extract on Breast Cancer Cell Line (T47D)’, Indonesian Journal of Biotechnology, 19(1), p. 71. doi: 10.22146/ijbiotech.8636.

Oh, S.-H., Choi, S.-Y., Choi, H.-J., Ryu, H.-M., Kim, Y.-J., Jung, H.-Y., Cho, J.-H., Kim, C.-D., Park, S.-H., Kwon, T.-H. and Kim, Y.-L. (2019) ‘The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia’, The FASEB Journal, 33(6), pp. 7301–7314. doi: 10.1096/fj.201802415RR.

Pontius, J., Richelle, J. and Wodak, S. J. (1996) ‘Deviations from Standard Atomic Volumes as a Quality Measure for Protein Crystal Structures’, Journal of Molecular Biology, 264(1), pp. 121–136. doi: 10.1006/jmbi.1996.0628.

Reuter, S., Gupta, S. C., Chaturvedi, M. M. and Aggarwal, B. B. (2010) ‘Oxidative stress, inflammation, and cancer: How are they linked?’, Free Radical Biology and Medicine, 49(11), pp. 1603–1616. doi: 10.1016/j.freeradbiomed.2010.09.006.

Rodríguez-García, C., Sánchez-Quesada, C. and Gaforio, J. J. (2019) ‘Dietary Flavonoids as Cancer Chemopreventive Agents: An Updated Review of Human Studies’, Antioxidants, 8(5), p. 137. doi: 10.3390/antiox8050137.

Subramanian, P., Mendez, E. F. and Becerra, S. P. (2016) ‘A Novel Inhibitor of 5-Lipoxygenase (5-LOX) Prevents Oxidative Stress–Induced Cell Death of Retinal Pigment Epithelium (RPE) Cells’, Investigative Opthalmology & Visual Science, 57(11), p. 4581. doi: 10.1167/iovs.15-19039.

Wang, Y., Branicky, R., Noë, A. and Hekimi, S. (2018) ‘Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling’, Journal of Cell Biology, 217(6), pp. 1915–1928. doi: 10.1083/jcb.201708007.

Weinberg, F. and Chandel, N. S. (2009) ‘Reactive oxygen species-dependent signaling regulates cancer’, Cellular and Molecular Life Sciences, 66(23), pp. 3663–3673. doi: 10.1007/s00018-009-0099-y.

Wlodawer, A. (2017) ‘Stereochemistry and Validation of Macromolecular Structures’, in, pp. 595–610. doi: 10.1007/978-1-4939-7000-1_24.

DOI: https://doi.org/10.22146/mot.70177

Article Metrics

Abstract views : 1012 | views : 1172


  • There are currently no refbacks.

Copyright (c) 2021 Majalah Obat Tradisional

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

©Majalah Obat Tradisional (Traditional Medicine Journal)
 ISSN 2406-9086
Faculty of Pharmacy
Universitas Gadjah Mada