ANTIHIPERPIGMENTASI Hylocereus costaricensis MELALUI INHIBISI TIROSINASE: STUDI NETWORK PHARMACOLOGY DAN MOLECULAR DOCKING
Abstrak
Hiperpigmentasi terjadi akibat peningkatan melanogenesis dan pengaruh stres oksidatif, sehingga diperlukan kandidat agen depigmentasi yang efektif dan aman. Penelitian ini bertujuan mengidentifikasi kandidat senyawa aktif dari Hylocereus costaricensis, memetakan target serta jalur molekuler hiperpigmentasi melalui network pharmacology, dan mengevaluasi potensi interaksi senyawa terpilih pada target melanogenesis menggunakan molecular docking. Metode mencakup penyaringan senyawa dan evaluasi drug-likeness/ADMET, prediksi target senyawa dan gen terkait hiperpigmentasi, konstruksi jaringan senyawa–target–penyakit serta protein–protein interaction, analisis topologi dan pengayaan GO/KEGG, kemudian docking pada TYRP1 (PDB: 5M8O). Lima kandidat utama, yaitu 2,2-dimethyl-3-phenylpropanoic acid, ferulic acid, o-coumaric acid, p-coumaric acid, dan vanillic acid telah memenuhi kriteria awal. Network pharmacology menyoroti mekanisme multi-target dengan node kunci AKT1, EGFR, PIK3CA, TYR, dan CDK4 serta keterlibatan jalur pensinyalan yang relevan dengan pigmentasi dan respons stres oksidatif. Molecular docking menunjukkan afinitas cukup baik dengan energi ikat sekitar −6,551 hingga −6,184 kkal/mol dan konstanta inhibisi terestimasi 15,779 hingga 29,315 µM, dengan kandidat terbaik 2,2-dimethyl-3-phenylpropanoic acid. Secara keseluruhan, integrasi network pharmacology dan molecular docking memberikan prioritas kandidat dan target untuk pengembangan agen antihiperpigmentasi berbasis H. costaricensis, namun temuan ini bersifat pendahuluan dan memerlukan validasi eksperimental serta penguatan mekanistik lanjutan.
Referensi
Alifah, L. H., Jatmika, C., dan Hayun, H. (2023). Exploration of Ferulic Acid and Its Derivatives as Potent Anti-Tyrosinase: A Systematic Review. Egyptian Journal of Chemistry, 0(0), 0–0. https://doi.org/10.21608/ejchem.2023.229107.8427
Allouche, J., Rachmin, I., Adhikari, K., Pardo, L. M., Lee, J. H., McConnell, A. M., Kato, S., Fan, S., Kawakami, A., Suita, Y., Wakamatsu, K., Igras, V., Zhang, J., Navarro, P. P., Lugo, C. M., Noonan, H. R., Christie, K. A., Itin, K., Mujahid, N., … Roider, E. (2021). NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell, 184(16), 4268-4283.e20. https://doi.org/10.1016/j.cell.2021.06.022
An, S. M., Koh, J., dan Boo, Y. C. (2010). p‐coumaric acid not only inhibits human tyrosinase activity in vitro but also melanogenesis in cells exposed to UVB. Phytotherapy Research, 24(8), 1175–1180. https://doi.org/10.1002/ptr.3095
Baber, M. A., Crist, C. M., Devolve, N. L., dan Patrone, J. D. (2023). Tyrosinase Inhibitors: A Perspective. Molecules, 28(15), 5762. https://doi.org/10.3390/molecules28155762
Baell, J. B., dan Holloway, G. A. (2010). New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. Journal of Medicinal Chemistry, 53(7), 2719–2740. https://doi.org/10.1021/jm901137j
Bao, M., Gempeler, M., dan Campiche, R. (2025). Melanosome Transport and Processing in Skin Pigmentation: Mechanisms and Targets for Pigmentation Modulation. International Journal of Molecular Sciences, 26(17), 8630. https://doi.org/10.3390/ijms26178630
Byun, K.-A., Lee, S. Y., Oh, S., Batsukh, S., Jang, J.-W., Lee, B.-J., Rheu, K., Li, S., Jeong, M.-S., Son, K. H., dan Byun, K. (2024). Fermented Fish Collagen Attenuates Melanogenesis via Decreasing UV-Induced Oxidative Stress. Marine Drugs, 22(9), 421. https://doi.org/10.3390/md22090421
Caminero Gomes Soares, A., Marques Sousa, G. H., Calil, R. L., dan Goulart Trossini, G. H. (2023). Absorption matters: A closer look at popular oral bioavailability rules for drug approvals. Molecular Informatics, 42(11). https://doi.org/10.1002/minf.202300115
Coelho, V. S., de Moura, D. G., Aguiar, L. L., Ribeiro, L. V., Silva, V. D. M., da Veiga Correia, V. T., Melo, A. C., Silva, M. R., de Paula, A. C. C. F. F., de Araújo, R. L. B., dan Melo, J. O. F. (2024). The Profile of Phenolic Compounds Identified in Pitaya Fruits, Health Effects, and Food Applications: An Integrative Review. Plants, 13(21), 3020. https://doi.org/10.3390/plants13213020
Contardi, M., Lenzuni, M., Fiorentini, F., Summa, M., Bertorelli, R., Suarato, G., dan Athanassiou, A. (2021). Hydroxycinnamic Acids and Derivatives Formulations for Skin Damages and Disorders: A Review. Pharmaceutics, 13(7), 999. https://doi.org/10.3390/pharmaceutics13070999
Daina, A., Michielin, O., dan Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research, 47(W1), W357–W364. https://doi.org/10.1093/nar/gkz382
Dass, K., Prakash, N., Manogar, P., dan Murugesan, R. (2024). Current insights and future perspectives of In silico molecular docking in dengue virus proteins inhibition: A review. Aspects of Molecular Medicine, 4, 100050. https://doi.org/10.1016/j.amolm.2024.100050
Gillbro, J. M., dan Olsson, M. J. (2011). The melanogenesis and mechanisms of skin‐lightening agents – existing and new approaches. International Journal of Cosmetic Science, 33(3), 210–221. https://doi.org/10.1111/j.1468-2494.2010.00616.x
Han, S.-Y., Jang, T.-W., Park, H.-J., Oh, S.-S., Lee, J.-B., Myoung, S.-M., dan Park, J.-H. (2022). Nypa fruticans Wurmb inhibits melanogenesis in isobutylmethylxanthine treated melanoma via the PI3K/AKT/mTOR/CREB and MAPK signaling pathways. Experimental and Therapeutic Medicine, 24(6), 754. https://doi.org/10.3892/etm.2022.11691
Hopkins, A. L. (2008). Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology, 4(11), 682–690. https://doi.org/10.1038/nchembio.118
Hosseini, M., Chen, W., Xiao, D., dan Wang, C. (2021). Computational molecular docking and virtual screening revealed promising SARS-CoV-2 drugs. Precision Clinical Medicine, 4(1), 1–16. https://doi.org/10.1093/pcmedi/pbab001
Hung, C., Nguyen, T. T. T., Poulikakos, P. I., dan Polsky, D. (2025). Recent Developments in Targeting the Cell Cycle in Melanoma. Cancers, 17(8), 1291. https://doi.org/10.3390/cancers17081291
Jang, S., Ha, C.-W., Kim, S.-H., Choi, J. H., Namkoong, S., Hong, S., Koo, H. J., Kim, Y.-K., Hadiwidjaja, M., Lee, S. R., dan Sohn, E.-H. (2024). Dual suppressive effect of p-coumaric acid on pigmentation in B16F10 cells. Molecular dan Cellular Toxicology, 20(4), 1011–1023. https://doi.org/10.1007/s13273-024-00430-0
Jin, W., Stehbens, S. J., Barnard, R. T., Blaskovich, M. A. T., dan Ziora, Z. M. (2024). Dysregulation of tyrosinase activity: a potential link between skin disorders and neurodegeneration. Journal of Pharmacy and Pharmacology, 76(1), 13–22. https://doi.org/10.1093/jpp/rgad107
Kabir, A., dan Muth, A. (2022). Polypharmacology: The science of multi-targeting molecules. Pharmacological Research, 176, 106055. https://doi.org/10.1016/j.phrs.2021.106055
Lai, X., Wichers, H. J., Soler‐Lopez, M., dan Dijkstra, B. W. (2017). Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis. Angewandte Chemie International Edition, 56(33), 9812–9815. https://doi.org/10.1002/anie.201704616
Lai, X., Wichers, H. J., Soler-López, M., dan Dijkstra, B. W. (2020). Phenylthiourea Binding to Human Tyrosinase-Related Protein 1. International Journal of Molecular Sciences, 21(3), 915. https://doi.org/10.3390/ijms21030915
Le, N. L. (2022). Functional compounds in dragon fruit peels and their potential health benefits: a review. International Journal of Food Science dan Technology, 57(5), 2571–2580. https://doi.org/10.1111/ijfs.15111
Li, A., He, H., Chen, Y., Liao, F., Tang, J., Li, L., Fan, Y., Li, L., dan Xiong, L. (2023). Effects of donkey milk on UVB-induced skin barrier damage and melanin pigmentation: A network pharmacology and experimental validation study. Frontiers in Nutrition, 10. https://doi.org/10.3389/fnut.2023.1121498
Liu, J., Xu, X., Zhou, J., Sun, G., Li, Z., Zhai, L., Wang, J., Ma, R., Zhao, D., Jiang, R., dan Sun, L. (2023). Phenolic acids in Panax ginseng inhibit melanin production through bidirectional regulation of melanin synthase transcription via different signaling pathways. Journal of Ginseng Research, 47(6), 714–725. https://doi.org/10.1016/j.jgr.2023.05.002
Magiera, A., Kołodziejczyk-Czepas, J., dan Olszewska, M. A. (2025). Antioxidant and Anti-Inflammatory Effects of Vanillic Acid in Human Plasma, Human Neutrophils, and Non-Cellular Models In Vitro. Molecules, 30(3), 467. https://doi.org/10.3390/molecules30030467
Mulyati, A. H., Nurmayani, R., Widiastuti, D., Warnasih, S., dan Sinaga, S. E. (2025). Antioxidant Potential and Active Compound Identification of Hylocereus costaricensis and Hylocereus undatus Peel Extracts using LC-MS/MS. Chimica et Natura Acta, 13(2), 175–184. https://doi.org/10.24198/cna.v13.n2.61186
Nakamura, H., dan Fukuda, M. (2024). Establishment of a synchronized tyrosinase transport system revealed a role of Tyrp1 in efficient melanogenesis by promoting tyrosinase targeting to melanosomes. Scientific Reports, 14(1), 2529. https://doi.org/10.1038/s41598-024-53072-6
Oh, S.-Y., dan Hyun, C.-G. (2025). Umckalin Promotes Melanogenesis in B16F10 Cells Through the Activation of Wnt/β-Catenin and MAPK Signaling Pathways. Applied Biosciences, 4(2), 20. https://doi.org/10.3390/applbiosci4020020
Ohbayashi, N., dan Fukuda, M. (2020). Recent advances in understanding the molecular basis of melanogenesis in melanocytes. F1000Research, 9, 608. https://doi.org/10.12688/f1000research.24625.1
Pollock, S., Taylor, S., Oyerinde, O., Nurmohamed, S., Dlova, N., Sarkar, R., Galadari, H., Manela-Azulay, M., Chung, H. S., Handog, E., dan Kourosh, A. S. (2021). The dark side of skin lightening: An international collaboration and review of a public health issue affecting dermatology. International Journal of Women’s Dermatology, 7(2), 158–164. https://doi.org/10.1016/j.ijwd.2020.09.006
Shah, T. A., dan Etui, I. D. (2023). GEF #10810: Eliminating Mercury Skin Lightening Products Global Kick-off Meeting and Stakeholder Consultation. World Health Organisation Headquarters.
Touni, A. A., Shivde, R. S., Echuri, H., Abdel-Aziz, R. T. A., Abdel-Wahab, H., Kundu, R. V., dan Le Poole, I. C. (2023). Melanocyte-keratinocyte cross-talk in vitiligo. Frontiers in Medicine, 10. https://doi.org/10.3389/fmed.2023.1176781
Wagatsuma, T., Suzuki, E., Shiotsu, M., Sogo, A., Nishito, Y., Ando, H., Hashimoto, H., Petris, M. J., Kinoshita, M., dan Kambe, T. (2023). Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins. Communications Biology, 6(1), 403. https://doi.org/10.1038/s42003-023-04640-5
Xu, P., Yang, L., Lai, S., Yang, F., Kuroda, Y., Zhang, H., Tsuruta, D., dan Katayama, I. (2024). Effects of EGFR‐TKI on epidermal melanin unit integrity: Therapeutic implications for hypopigmented skin disorders. Pigment Cell dan Melanoma Research, 37(4), 514–529. https://doi.org/10.1111/pcmr.13171
Yang, H.-L., Lin, C.-P., Vudhya Gowrisankar, Y., Huang, P.-J., Chang, W.-L., Shrestha, S., dan Hseu, Y.-C. (2021). The anti-melanogenic effects of ellagic acid through induction of autophagy in melanocytes and suppression of UVA-activated α-MSH pathways via Nrf2 activation in keratinocytes. Biochemical Pharmacology, 185, 114454. https://doi.org/10.1016/j.bcp.2021.114454
Yu, Q., dan Fan, L. (2021). Understanding the combined effect and inhibition mechanism of 4-hydroxycinnamic acid and ferulic acid as tyrosinase inhibitors. Food Chemistry, 352, 129369. https://doi.org/10.1016/j.foodchem.2021.129369
Zolghadri, S., Bahrami, A., Hassan Khan, M. T., Munoz-Munoz, J., Garcia-Molina, F., Garcia-Canovas, F., dan Saboury, A. A. (2019). A comprehensive review on tyrosinase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1), 279–309. https://doi.org/10.1080/14756366.2018.1545767
Zolghadri, S., Beygi, M., Mohammad, T. F., Alijanianzadeh, M., Pillaiyar, T., Garcia-Molina, P., Garcia-Canovas, F., Munoz-Munoz, J., dan Saboury, A. A. (2023). Targeting tyrosinase in hyperpigmentation: Current status, limitations and future promises. Biochemical Pharmacology, 212, 115574. https://doi.org/10.1016/j.bcp.2023.115574
