Citrus peels contain various phytochemical active compounds such as flavonoids that are useful for antiaging cosmetic products. This study was conducted to identify the anti-collagenase and anti-elastase activities of flavonoid compounds in citrus peel and to determine the molecular interaction mechanism using the molecular docking method. The study was carried out through several stages, including preparation of enzyme macromolecules, preparation of flavonoid compound molecules, validation of molecular docking, identification of binding-free energy, visualization of interaction conformations, and predictions of molecular skin toxicity. The result showed that the flavonoid compounds in citrus peel (hesperidin, naringin, nobiletin, and tangeretin) could bind to collagenase and elastase enzymes. Naringin has the highest affinity for the collagenase enzyme with the binding-free energy of −9.52 kcal/mol, while nobiletin has the highest affinity for the elastase enzyme with the binding-free energy of −6.44 kcal/mol. Compared to EGCG (epigallocatechin gallate), the flavonoid compounds have a lower affinity for the collagenase enzyme but a higher affinity for elastase enzymes. Hydrogen bonds and the hydrophobic interactions dominate the interaction between citrus peel’s flavonoids against the enzymes. When applied to the skin, flavonoid compounds are predicted to have no risk of skin toxicity. The flavonoid compounds of citrus peels are expected to have anti-collagenase and anti-elastase activities.


Apraj, V. D., & Pandita, N. S. (2016). Evaluation of skin anti-aging potential of Citrus reticulata blanco peel. Pharmacognosy Research, 8(3), 160–168.

Azmi, N., Hashim, P., Hashim, D. M., Halimoon, N., & Nik Majid, N. M. (2014). Asian Pacific Journal of Tropical Biomedicine, 4(Suppl 1): S348–S352. https://doi.org/10.12980/APJTB.4.2014C1166

Bakalova, S., & Kaneti, J. (2000). Semi-empirical AM1 calculation of the solvent effect on the fluorescence spectra of some dihydroquinolinones. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 56(8): 1443–1452. https://doi.org/10.1016/S1386-1425(99)00282-6

Boyken, S. E., Chen, Z., Groves, B., Langan, R. A., Oberdorfer, G., Ford, A., Gilmore, J. M., Xu, C., DiMaio, F., Pereira, J. H., Sankaran, B., Seelig, G., Zwart, P. H., & Baker, D. (2016). De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity, Science, 352( 6286), 680-687. https://doi.org/10.1126/science.aad8865

Chen, X. M., Tait, A. R., & Kitts, D. D. (2017). Flavonoid composition of orange peel and its association with antioxidant and anti-inflammatory activities. Food Chemistry, 218:15-21. https://doi.org/10.1016/j.foodchem.2016.09.016

Dar, A. M., & Mir, S. (2017). Molecular Docking: Approaches, Types, Applications and Basic Challenges. Journal of Analytical & Bioanalytical Techniques, 8(2): 356. https://doi.org/10.4172/2155-9872.1000356

Deshmukh, G. R., Kumar, K. H., Reddy, P. V. S., & Rao, B. S. (2012). In vitro skin corrosion: Human skin model test - A validation study. Toxicology in Vitro, 26(6): 1072–1074. https://doi.org/10.1016/j.tiv.2012.04.021

Eun Lee, K., Bharadwaj, S., Yadava, U., & Gu Kang, S. (2019). Evaluation of caffeine as inhibitor against collagenase, elastase and tyrosinase using in silico and in vitro approach. Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1): 927–936. https://doi.org/10.1080/14756366.2019.1596904

Fakih, T. M., & Dewi, M. L. (2020). Identifikasi Mekanisme Molekuler Senyawa Bioaktif Peptida Laut sebagai Kandidat Inhibitor Angiotensin-I Converting Enzyme (ACE). Jurnal Sains Farmasi & Klinis, 7(1): 76–82. https://doi.org/10.25077/jsfk.7.1.76-82.2020

Fitri, A. C. K., & Widyastuti, F. K. (2020). Perbandingan Metode Microwave Hydrodiffusion and Gravity (MHG) dan Microwave Steam Diffusion (MSDf) untuk Mengekstrak Minyak Atsiri dari Kulit Jeruk (Citrus aurantium L.). Jurnal Teknik Kimia USU, 9(2). https://doi.org/10.32734/jtk.v9i2.4302

Forli, S., Huey, R., Pique, M. E., Sanner, M. F., Goodsell, D. S., & Olson, A. J. (2016). Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nature Protocols, 11(5), 905–919. https://doi.org/10.1038/nprot.2016.051

Ganceviciene, R., Liakou, A. I., Theodoridis, A., Makrantonaki, E., & Zouboulis, C. C. (2012). Skin antiaging strategies. In Dermato-Endocrinology, 4(3): 308–319. https://doi.org/10.4161/derm.22804

Gómez-Mejía, E., Rosales-Conrado, N., León-González, M. E., & Madrid, Y. (2019). Citrus peels waste as a source of value-added compounds: Extraction and quantification of bioactive polyphenols. Food Chemistry, 295: 289–299. https://doi.org/10.1016/j.foodchem.2019.05.136

Han, Y., Zhang, J., Hu, C. Q., Zhang, X., Ma, B., & Zhang, P. (2019). In silico ADME and toxicity prediction of ceftazidime and its impurities. Frontiers in Pharmacology, 10: 434. https://doi.org/10.3389/fphar.2019.00434

Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P.A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2021). PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Research, 49(1): 1388–1395. https://doi.org/10.1093/nar/gkaa971

Lv, X., Zhao, S., Ning, Z., Zeng, H., Shu, Y., Tao, O., Xiao, C., Lu, C., & Liu, Y. (2015). Citrus fruits as a treasure trove of active natural metabolites that potentially provide benefits for human health. In Chemistry Central Journal, 9: 68. https://doi.org/10.1186/s13065-015-0145-9

M’hiri, N., Ioannou, I., Ghoul, M., & Mihoubi Boudhrioua, N. (2017). Phytochemical characteristics of citrus peel and effect of conventional and nonconventional processing on phenolic compounds: A review. In Food Reviews International, 33(6). https://doi.org/10.1080/87559129.2016.1196489

Mobley, D. L., & Klimovich, P. V. (2012). Perspective: Alchemical free energy calculations for drug discovery. In Journal of Chemical Physics, 137(23): 230901. https://doi.org/10.1063/1.4769292

Muttaqin, F. Z., Fakih, T. M., & Muhammad, H. N. (2017). Molecular docking, molecular dynamics, and in silico toxicity prediction studies of coumarin, N-Oxalylglycine, organoselenium, organosulfur, and pyridine derivatives as histone lysine demethylase inhibitors. Asian Journal of Pharmaceutical and Clinical Research, 10(12): 212. https://doi.org/10.22159/ajpcr.2017.v10i12.19348

Osorio, E., Bravo, K., Cardona, W., Yepes, A., Osorio, E. H., & Coa, J. C. (2019). Antiaging activity, molecular docking, and prediction of percutaneous absorption parameters of quinoline–hydrazone hybrids. Medicinal Chemistry Research, 28(11). https://doi.org/10.1007/s00044-019-02427-0

Pitaloka, D. A. E., Ramadhan, D. S. F., Arfan, Chaidir, L., & Fakih, T. M. (2021). Docking-based virtual screening and molecular dynamics simulations of quercetin analogs as enoyl-acyl carrier protein reductase (Inha) inhibitors of mycobacterium tuberculosis. Scientia Pharmaceutica, 89(2): 20. https://doi.org/10.3390/scipharm89020020

Rafiq, S., Kaul, R., Sofi, S. A., Bashir, N., Nazir, F., & Ahmad Nayik, G. (2018). Citrus peel as a source of functional ingredient: A review. In Journal of the Saudi Society of Agricultural Sciences, 17(4): 351–358. https://doi.org/10.1016/j.jssas.2016.07.006

Seitz, F., Bundschuh, M., Rosenfeldt, R. R., & Schulz, R. (2013). Nanoparticle toxicity in Daphnia magna reproduction studies: The importance of test design. Aquatic Toxicology, 126: 163–168. https://doi.org/10.1016/j.aquatox.2012.10.015

Singh, J., Chopra, D., Dwivedi, A., & Ray, R. S. (2018). Photoaging. In Photocarcinogenesis and Photoprotection. https://doi.org/10.1007/978-981-10-5493-8_7

Tauro, M., Laghezza, A., Loiodice, F., Piemontese, L., Caradonna, A., Capelli, D., Montanari, R., Pochetti, G., Di Pizio, A., Agamennone, M., Campestre, C., & Tortorella, P. (2016). Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(sup4): 25–37. https://doi.org/10.1080/14756366.2016.1217853

Thring, T. S. A., Hili, P., & Naughton, D. P. (2009). Anti-collagenase, anti-elastase and anti-oxidant activities of extracts from 21 plants. BMC Complementary and Alternative Medicine, 9: 27. https://doi.org/10.1186/1472-6882-9-27

Ugur, I., Marion, A., Parant, S., Jensen, J. H., & Monard, G. (2014). Rationalization of the p K a values of alcohols and thiols using atomic charge descriptors and its application to the prediction of amino acid p K a’s. Journal of Chemical Information and Modeling, 54(8): 2200–2213. https://doi.org/10.1021/ci500079w

Vijayakumar, R., Gani, S. S. A., & Mokhtar, N. F. (2017). Anti-elastase, anti-collagenase and antimicrobial activities of the underutilized red pitaya peel: An in vitro study for antiaging applications. Asian Journal of Pharmaceutical and Clinical Research, 10(8): 251. https://doi.org/10.22159/ajpcr.2017.v10i8.19048

Von Nussbaum, F., Li, V. M., Meibom, D., Anlauf, S., Bechem, M., Delbeck, M., Gerisch, M., Harrenga, A., Karthaus, D., Lang, D., Lustig, K., Mittendorf, J., Schäfer, M., Schäfer, S., & Schamberger, J. (2016). Potent and Selective Human Neutrophil Elastase Inhibitors with Novel Equatorial Ring Topology: In vivo Efficacy of the Polar Pyrimidopyridazine BAY-8040 in a Pulmonary Arterial Hypertension Rat Model. ChemMedChem, 11(2): 199–206. https://doi.org/10.1002/cmdc.201500269

Xu, R. R., Pei, Z. T., Wang, W. Q., Zhang, M., Zhang, L. L., Zhang, J., Wang, W. Q., Sun, L. W., & Zhang, Y. M. (2020). Assessment of biological toxicity and ecological safety for urban black-odor river remediation. International Journal of Environmental Research and Public Health, 17(3): 1025. https://doi.org/10.3390/ijerph17031025

Zhu, K., Borrelli, K. W., Greenwood, J. R., Day, T., Abel, R., Farid, R. S., & Harder, E. (2014). Docking covalent inhibitors: A parameter free approach to pose prediction and scoring. Journal of Chemical Information and Modeling, 54(7): 1932–1940. https://doi.org/10.1021/ci500118s



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