The Inhibitory Effect of Several Compounds of Citrus Sp. on Dipeptidyl Peptidase-4 (DPP-4) Enzymes: In Vitro and In Silico Studies
Keywords:
Citrus peel, Antioxidant, Diabetes Mellitus, DPP-4 inhibitory activity
Abstract
Diabetes mellitus is a chronic disease that has an increasing prevalence over the years. One of the treatment approaches for diabetes mellitus is to inhibit the DPP-4 enzyme, which plays an important role in glucose metabolism. The use of citrus peel as a rich source of flavonoids can be an antioxidant that has a relation with inhibitory activity on the DPP-4 enzyme. This study aims to determine the potential of citrus peel based on its phytochemical content from three locations on DPP-4 enzyme inhibitory activity associated with antioxidant activity in vitro and in silico. Since this activity is closely related to antioxidant activity, a DPPH assay was measured and the IC50 (ppm) was evaluated. DPP-4 inhibition was evaluated by the percent of relative inhibition values of flavonoids, scopoletin, vildagliptin, and sitagliptin. The highest IC50 value of antioxidant in the citrus peel extract was found in Yogyakarta at 3271.7 ppm, and quercitrin as a flavonoid standard at 5.2 ppm. The highest DPP-4 enzyme inhibitory activities were found in the Yogyakarta extract and scopoletin standard by 75.3% and 94.9%, respectively. The DPP-4 enzyme inhibitory activity of flavonoids in citrus peel can be described in silico and indicates promising potential as DPP-4 inhibitors. Several flavonoids reported to be contained in citrus peel have antioxidant activity that can be directly correlated with DPP-4 inhibitor activity in vitro and in silico.
References
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Nugroho, A. E., Hermawan, A., Nastiti, K., Suven, Elisa, P., Hadibarata, T., & Meiyanto, E. (2012). Immunomodulatory effects of hexane insoluble fraction of Ficus septica Burm. F. in doxorubicin-treated rats. Asian Pacific Journal of Cancer Prevention : APJCP, 13(11), 5785–5790.https://doi.org/10.7314/apjcp.2012.13.11.5785
Nugroho, A. E., Riyanto, S., Sukari, M. A., & Maeyama, K. (2011). Anti-allergic effects of Marmin, a coumarine isolated from Aegle marmelos Correa: In vitro study. International Journal of Phytomedicine, 3(1), 84–97.
Nurrochmad, A., Ikawati, M., Sari, I. P., Murwanti, R., & Nugroho, A. E. (2015). Immunomodulatory Effects of Ethanolic Extract of Thyphonium flagelliforme (Lodd) Blume in Rats Induced by Cyclophosphamide. Journal of Evidence-Based Complementary & Alternative Medicine, 20(3), 167–172. https://doi.org/10.1177/2156587214568347
Pan, J., Zhang, Q., Zhang, C., Yang, W., Liu, H., Lv, Z., Liu, J., & Jiao, Z. (2022). Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure-Activity Relationship, Kinetics and Interaction Mechanism. Frontiers in Nutrition, 9(May), 1–17. https://doi.org/10.3389/fnut.2022.892426
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Ramírez-Pelayo, C., Martínez-Quiñones, J., Gil, J., & Durango, D. (2019). Coumarins from the peel of citrus grown in Colombia: composition, elicitation and antifungal activity. Heliyon, 5(6). https://doi.org/10.1016/j.heliyon.2019.e01937
Ramírez, D., & Caballero, J. (2018). Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Molecules, 23(5), 1038. https://doi.org/10.3390/molecules23051038
Röhrborn, D., Wronkowitz, N., & Eckel, J. (2015). DPP4 in Diabetes. Frontiers in Immunology, 6, 386. https://doi.org/10.3389/fimmu.2015.00386
Scapin, G. (2015). Structural Chemistry and Molecular Modeling in the Design of DPP4 Inhibitors. NATO Science for Peace and Security Series A: Chemistry and Biology, 38, 53–67. https://doi.org/10.1007/978-94-017-9719-1_5
Setha, B., Gaspersz, F. F., Idris, A. P. S., Rahman, S., & Mailoa, M. N. (2013). Potential Of Seaweed Padina Sp. As A Source Of Antioxidant. International Journal of Scientific & Technology Research, 2(6), 221–224.
Singh, A. K., Patel, P. K., Choudhary, K., Joshi, J., Yadav, D., & Jin, J. O. (2020). Quercetin and coumarin inhibit dipeptidyl peptidase-IV and exhibit antioxidant properties: In silico, in vitro, and ex vivo. Biomolecules, 10(2), 1–14. https://doi.org/10.3390/biom10020207
Soomro, M. A., Khan, S., Majid, A., Bhatti, S., Perveen, S., & Phull, A. R. (2024). Pectin as a biofunctional food: a comprehensive overview of its therapeutic effects and antidiabetic-associated mechanisms. Discover Applied Sciences, 6(6). https://doi.org/10.1007/s42452-024-05968-1
Tanoey, J., & Becher, H. (2021). Diabetes prevalence and risk factors of early-onset adult diabetes: results from the Indonesian family life survey. Global Health Action, 14(1), 200114. https://doi.org/10.1080/16549716.2021.2001144
Taylor, S. I., Yazdi, Z. S., & Beitelshees, A. L. (2021). Pharmacological treatment of hyperglycemia in type 2 diabetes. The Journal of Clinical Investigation, 131(2). https://doi.org/10.1172/JCI142243
Tocmo, R., Pena-Fronteras, J., Calumba, K. F., Mendoza, M., & Johnson, J. J. (2020). Valorization of pomelo (Citrus grandis Osbeck) peel: A review of current utilization, phytochemistry, bioactivities, and mechanisms of action. Comprehensive Reviews in Food Science and Food Safety, 19(4), 1969–2012. https://doi.org/10.1111/1541-4337.12561
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Chen, S. Y., Kong, X. Q., Zhang, K. F., Luo, S., Wang, F., & Zhang, J. J. (2022). DPP4 as a Potential Candidate in Cardiovascular Disease. Journal of Inflammation Research, 15(September), 5457–5469. https://doi.org/10.2147/JIR.S380285
de Menezes, B. B., Frescura, L. M., Duarte, R., Villetti, M. A., & da Rosa, M. B. (2021). A critical examination of the DPPH method: Mistakes and inconsistencies in stoichiometry and IC50 determination by UV–Vis spectroscopy. Analytica Chimica Acta, 1157, 338398. https://doi.org/10.1016/j.aca.2021.338398
Duarte, A. M., Guarino, M. P., Barroso, S., & Gil, M. M. (2020). Phytopharmacological Strategies in the Management of Type 2 Diabetes Mellitus. Foods (Basel, Switzerland), 9(3). https://doi.org/10.3390/foods9030271
Fan, J., Johnson, M. H., Lila, M. A., Yousef, G., & de Mejia, E. G. (2013). Berry and Citrus Phenolic Compounds Inhibit Dipeptidyl Peptidase IV: Implications in Diabetes Management. Evidence-Based Complementary and Alternative Medicine : ECAM, 2013, 479505. https://doi.org/10.1155/2013/479505
Foti, M. C. (2015). Use and Abuse of the DPPH(•) Radical. Journal of Agricultural and Food Chemistry, 63(40), 8765–8776. https://doi.org/10.1021/acs.jafc.5b03839
Gillespie, K. M. (2006). Type 1 diabetes: pathogenesis and prevention. CMAJ : Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 175(2), 165–170. https://doi.org/10.1503/cmaj.060244
Gorinstein, S., Martin-Belloso, O., Park, Y.-S., Haruenkit, R., Lojek, A., Ĉı́ž, M., Caspi, A., Libman, I., & Trakhtenberg, S. (2001). Comparison of some biochemical characteristics of different Citrus fruits. Food Chemistry, 74, 309–315. https://doi.org/10.1016/S0308-8146(01)00157-1
IDF. (2021). Five questions on the IDF Diabetes Atlas. Diabetes Research and Clinical Practice, 102(2), 147–148. https://doi.org/10.1016/j.diabres.2013.10.013
Indriyani, N. N., Anshori, J. Al, Permadi, N., Nurjanah, S., & Julaeha, E. (2023). Bioactive Components and Their Activities from Different Parts of Citrus aurantifolia (Christm.) Swingle for Food Development. Foods, 12(10). https://doi.org/10.3390/foods12102036
Lehrke, M., & Marx, N. (2017). Diabetes Mellitus and Heart Failure. The American Journal of Medicine, 130(6S), S40–S50. https://doi.org/10.1016/j.amjmed.2017.04.010
Li, X., Jiang, Q., Wang, T., Liu, J., & Chen, D. (2016). Comparison of the antioxidant effects of quercitrin and isoquercitrin: Understanding the role of the 6″-OH group. Molecules, 21(9). https://doi.org/10.3390/molecules21091246
Lin, C., Zhu, C., Hu, M., Wu, A., Zerendawa, B., & Suolangqimei, K. (2014). Structure-activity Relationships of Antioxidant Activity in vitro about Flavonoids Isolated from Pyrethrum Tatsienense. Journal of Intercultural Ethnopharmacology, 3(3), 123. https://doi.org/10.5455/jice.20140619030232
Loizzo, M. R., Tundis, R., Bonesi, M., Menichini, F., De Luca, D., Colica, C., & Menichini, F. (2012). Evaluation of Citrus aurantifolia peel and leaves extracts for their chemical composition, antioxidant and anti-cholinesterase activities. Journal of the Science of Food and Agriculture, 92(15), 2960–2967. https://doi.org/10.1002/jsfa.5708
Magliano, D. J., Islam, R. M., Barr, E. L. M., Gregg, E. W., Pavkov, M. E., Harding, J. L., Tabesh, M., Koye, D. N., & Shaw, J. E. (2019). Trends in incidence of total or type 2 diabetes: systematic review. BMJ, 366, l5003. https://doi.org/10.1136/bmj.l5003
Marbun, P., Hakim, A. R., Ujiantari, N. S. O., Sudarmanto, B. S. A., & Nugroho, A. E. (2023). In Silico Pharmacokinetics Study of 2,5-Dibenzylidenecyclopentanone Analogs as Mono-Ketone Versions of Curcumin. BIO Web of Conferences, 75. https://doi.org/10.1051/bioconf/20237504002
Mare, R., Pujia, R., Maurotti, S., Greco, S., Cardamone, A., Coppoletta, A. R., Bonacci, S., Procopio, A., & Pujia, A. (2023). Assessment of Mediterranean Citrus Peel Flavonoids and Their Antioxidant Capacity Using an Innovative UV-Vis Spectrophotometric Approach. Plants, 12(23), 1–15. https://doi.org/10.3390/plants12234046
Megawati, A., Nurrochmad, A., Nugroho, A. E., Lukitaningsih, E., Marbun, P., Tengah, J., Mada, U. G., Mada, U. G., & Mada, U. G. (2024). eISSN: 2503-0310. 19(2), 320–331.
Moufida, S., & Marzouk, B. (2003). Biochemical characterization of blood orange, sweet orange, lemon, bergamot, and bitter orange. Phytochemistry, 62(8), 1283–1289. https://doi.org/10.1016/s0031-9422(02)00631-3
Munteanu, I. G., & Apetrei, C. (2021). Analytical methods used in determining antioxidant activity: A review. International Journal of Molecular Sciences, 22(7). https://doi.org/10.3390/ijms22073380
Mutmainah, Susilowati, R., Rahmawati, N., & Nugroho, A. E. (2014). Gastroprotective effects of the combination of hot water extracts of turmeric (Curcuma domestica L.), cardamom pods (Ammomum compactum S.), and sembung leaf (Blumea balsamifera DC.) against aspirin-induced gastric ulcer model in rats. Asian Pacific Journal of Tropical Biomedicine, 4, S500–S504. https://doi.org/https://doi.org/10.12980/APJTB.4.2014C972
Nugroho, A. E., Hermawan, A., Nastiti, K., Suven, Elisa, P., Hadibarata, T., & Meiyanto, E. (2012). Immunomodulatory effects of hexane insoluble fraction of Ficus septica Burm. F. in doxorubicin-treated rats. Asian Pacific Journal of Cancer Prevention : APJCP, 13(11), 5785–5790.https://doi.org/10.7314/apjcp.2012.13.11.5785
Nugroho, A. E., Riyanto, S., Sukari, M. A., & Maeyama, K. (2011). Anti-allergic effects of Marmin, a coumarine isolated from Aegle marmelos Correa: In vitro study. International Journal of Phytomedicine, 3(1), 84–97.
Nurrochmad, A., Ikawati, M., Sari, I. P., Murwanti, R., & Nugroho, A. E. (2015). Immunomodulatory Effects of Ethanolic Extract of Thyphonium flagelliforme (Lodd) Blume in Rats Induced by Cyclophosphamide. Journal of Evidence-Based Complementary & Alternative Medicine, 20(3), 167–172. https://doi.org/10.1177/2156587214568347
Pan, J., Zhang, Q., Zhang, C., Yang, W., Liu, H., Lv, Z., Liu, J., & Jiao, Z. (2022). Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure-Activity Relationship, Kinetics and Interaction Mechanism. Frontiers in Nutrition, 9(May), 1–17. https://doi.org/10.3389/fnut.2022.892426
Parmar, H. S., Jain, P., Chauhan, D. S., Bhinchar, M. K., Munjal, V., Yusuf, M., Choube, K., Tawani, A., Tiwari, V., Manivannan, E., & Kumar, A. (2012). DPP-4 inhibitory potential of naringin: An in silico, in vitro and in vivo study. Diabetes Research and Clinical Practice, 97(1), 105–111. https://doi.org/10.1016/j.diabres.2012.02.011
Permadi, N., Nurzaman, M., Doni, F., & Julaeha, E. (2024). Elucidation of the composition, antioxidant, and antimicrobial properties of essential oil and extract from Citrus aurantifolia (Christm.) Swingle peel. Saudi Journal of Biological Sciences, 31(6), 103987. https://doi.org/10.1016/j.sjbs.2024.103987
Pissarnitski, D. A., Zhao, Z., Cole, D., Wu, W. L., Domalski, M., Clader, J. W., Scapin, G., Voigt, J., Soriano, A., Kelly, T., Powles, M. A., Yao, Z., & Burnett, D. A. (2016). Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors. Bioorganic and Medicinal Chemistry, 24(21), 5534–5545. https://doi.org/10.1016/j.bmc.2016.09.007
Ramírez-Pelayo, C., Martínez-Quiñones, J., Gil, J., & Durango, D. (2019). Coumarins from the peel of citrus grown in Colombia: composition, elicitation and antifungal activity. Heliyon, 5(6). https://doi.org/10.1016/j.heliyon.2019.e01937
Ramírez, D., & Caballero, J. (2018). Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Molecules, 23(5), 1038. https://doi.org/10.3390/molecules23051038
Röhrborn, D., Wronkowitz, N., & Eckel, J. (2015). DPP4 in Diabetes. Frontiers in Immunology, 6, 386. https://doi.org/10.3389/fimmu.2015.00386
Scapin, G. (2015). Structural Chemistry and Molecular Modeling in the Design of DPP4 Inhibitors. NATO Science for Peace and Security Series A: Chemistry and Biology, 38, 53–67. https://doi.org/10.1007/978-94-017-9719-1_5
Setha, B., Gaspersz, F. F., Idris, A. P. S., Rahman, S., & Mailoa, M. N. (2013). Potential Of Seaweed Padina Sp. As A Source Of Antioxidant. International Journal of Scientific & Technology Research, 2(6), 221–224.
Singh, A. K., Patel, P. K., Choudhary, K., Joshi, J., Yadav, D., & Jin, J. O. (2020). Quercetin and coumarin inhibit dipeptidyl peptidase-IV and exhibit antioxidant properties: In silico, in vitro, and ex vivo. Biomolecules, 10(2), 1–14. https://doi.org/10.3390/biom10020207
Soomro, M. A., Khan, S., Majid, A., Bhatti, S., Perveen, S., & Phull, A. R. (2024). Pectin as a biofunctional food: a comprehensive overview of its therapeutic effects and antidiabetic-associated mechanisms. Discover Applied Sciences, 6(6). https://doi.org/10.1007/s42452-024-05968-1
Tanoey, J., & Becher, H. (2021). Diabetes prevalence and risk factors of early-onset adult diabetes: results from the Indonesian family life survey. Global Health Action, 14(1), 200114. https://doi.org/10.1080/16549716.2021.2001144
Taylor, S. I., Yazdi, Z. S., & Beitelshees, A. L. (2021). Pharmacological treatment of hyperglycemia in type 2 diabetes. The Journal of Clinical Investigation, 131(2). https://doi.org/10.1172/JCI142243
Tocmo, R., Pena-Fronteras, J., Calumba, K. F., Mendoza, M., & Johnson, J. J. (2020). Valorization of pomelo (Citrus grandis Osbeck) peel: A review of current utilization, phytochemistry, bioactivities, and mechanisms of action. Comprehensive Reviews in Food Science and Food Safety, 19(4), 1969–2012. https://doi.org/10.1111/1541-4337.12561
WHO. (2016). Global Report on Diabetes. Isbn, 978, 88. https://doi.org/ISBN 978 92 4 156525 7
Published
2025-07-16
How to Cite
Pribadi, F. H., Marbun, P., Endro Nugroho, A., Bayumurti, Y., & Retnoaji, B. (2025). The Inhibitory Effect of Several Compounds of Citrus Sp. on Dipeptidyl Peptidase-4 (DPP-4) Enzymes: In Vitro and In Silico Studies. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.18429
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Section
Research Article
