PENAMBATAN MOLEKUL SENYAWA AKTIF CURCUMA XANTHORRHIZA ROXB KANDIDAT ANTI KANKER KOLOREKTAL TERHADAP RESEPTOR LYMPHOCYTE-SPECIFIC PROTEIN TYROSINE KINASE
Isi Artikel Utama
Temulawak (Curcuma xanthorrhiza Roxb) mengandung minyak atsiri dan senyawa kurkuminoid yang bersifat antikanker. Metabolit pada temulawak dapat menjadi kandidat agen kemoterapi kanker kolorektal terhadap reseptor Lck pada sel epitel kolon. Tujuan penelitian ini untuk mengidentifikasi senyawa aktif yang berpotensi sebagai antikanker kolorektal yang terkandung dalam Temulawak (Curcuma xanthorrhiza Roxb) terhadap reseptor Lck melalui studi in silico metode penambatan molekuler. Studi ini dilakukan dengan cara prediksi Lipinski dengan LigandScout, Molecular docking melalui perangkat lunak AutoDock Tools 1.5.6., visualisasi menggunakan Biovia Discovery Studio 2021 Client, prediksi sifat ADMET menggunakan pkCSM. Hasil studi menunjukkan keempat senyawa memenuhi Lipinski's rule of five, hasil pengujian molecular docking dan visualisasi interaksi menunjukkan xanthorrhizol memiliki interaksi terbaik dengan energi -6,26 kkal/mol dan Ki 25,71 µM, terdapat dua ikatan hidrogen pada interaksi xanthorrhizol dengan reseptor Lck dan interaksi ini sama dengan ligan alami dan obat pembanding doxorubicin. Senyawa lainnya seperti curcumin dan bisdemethoxycurcumin pada memiliki potensi yang baik namun hanya memiliki satu kesamaan interaksi dengan ligan alami. Studi ADMET menunjukkan xanthorrhizol memiliki karakter absorpsi dan distribusi yang baik, metabolisme yang rendah, tidak mutagenik dan tidak karsinogenik pada mencit. Berdasarkan hasil penelitian, senyawa xanthorrhizol memiliki potensi yang paling baik, namun belum melampaui ligan alami untuk menjadi kandidat antikanker kolorektal dan memenuhi aturan Lipinski sehingga aman untuk diadministrasikan secara oral. Modifikasi struktur kimia diperlukan agar memiliki potensi yang lebih baik dibandingkan ligan alami.
Kata kunci: Curcuma xanthorrhiza Roxb, kanker kolorektal, Lck, in silico, penambatan molekuler
Abstract
Temulawak (Curcuma xanthorrhiza Roxb) contains essential oils and curcuminoid compounds that have anticancer properties. Metabolites in temulawak can be candidates for colorectal cancer chemotherapy agents against Lck receptors in colonic epithelial cells. The purpose of this study was to identify active compounds that have the potential to be colorectal anticancer agents contained in Temulawak (Curcuma xanthorrhiza Roxb) against Lck receptors through in silico studies of molecular docking methods. Methods: This study was conducted using the Lipinski prediction method with LigandScout, Molecular docking using AutoDock Tools 1.5.6 software., visualization using Biovia Discovery Studio 2021 Client, prediction of ADMET properties using pkCSM. The results of the study showed that the four compounds met Lipinski's rule of five, the results of molecular docking and visualization of interactions showed that xanthorrhizol had the best interaction with an energy of -6.26 kcal/mol and Ki 25.71 µM, there were two hydrogen bonds in the interaction of xanthorrhizol with the Lck receptor and this interaction was the same as the natural ligand and the reference drug doxorubicin. Other compounds such as curcumin and bisdemethoxycurcumin had good potential but only had one similarity in interaction with the natural ligand. The ADMET study showed that xanthorrhizol had good absorption and distribution characteristics, low metabolism, was non-mutagenic and non-carcinogenic in mice. Based on the results of the study, the xanthorrhizol compound had the best potential, but had not surpassed the natural ligand to become a candidate for colorectal anticancer and met Lipinski's rule so that it was safe to be administered orally. Modification of the chemical structure is needed to have better potential than the natural ligand.
Keywords: Curcuma xanthorrhiza Roxb, colorectal cancer, Lck, in silico, molecular docking
Agustin, T., & Sari, R. D. P. (2021). Efektivitas Nutrasetikal sebagai Agen Kemopreventif dalam Melawan Sel Kanker Payudara. Medical Profession Journal of Lampung, 10(4), 777-785.
Asnawi, A. et al. (2023). Penambatan Molekul dan Dinamika Molekul beberapa Fitokimia dari Acalypha Indica L. sebagai Inhibitor Matriks Metalloproteinase9, Jurnal Sains Farmasi & Klinis, 10(1), p. 62.
Batu, R. L., Tarigan, Y. N., Oktavia, O., Daulay, N. A. F., Lubis, T. H., Ginting, L., & Hasibuan, M. T. D. (2020). Hubungan Pengetahuan Sikap Wanita UsiaSubur Dalam Melakukan Deteksi Dini Kanker Servik. Indonesian Trust Health Journal, 3(2), 381-386.
Benet LZ, Hosey CM, Ursu O, Oprea TI. (2016). BDDCS, the Rule of 5 and drugability. Adv Drug Deliv. Rev. 101:89-98. doi: 10.1016/j.addr.2016.05.007. Epub 2016 May 13. PMID: 27182629; PMCID: PMC4910824.
Christine, C., F. Pebriani, et al 2022. In Silico Study of Ranti Plants Extract (Solanum nigrum) as JAK2 Inhibitor in Leukimia Lymphoblastic Disease. Indonesian Journal of Biological Pharmacy. 2(1), 10-21.
Dar, A. M., & Mir, S. (2017). Molecular Docking: Approaches, Types, Applications and Basic Challenges. Journal of Analytical & Bioanalytical Techniques, 8, 356.
De Oliveira, C. S., Lira, B. F., Falcao-Silva, V. D. S., Siqueira-Junior, J. P., Barbosa-Filho, J. M., & De Athayde-Filho, P. F. (2012). Synthesis, molecular properties prediction, and anti-staphylococcal activity of N-acylhydrazones and new 1,3,4-oxadiazole derivatives. Molecules, 17(5), 5095–5107.
Dos Santos, R. N., Ferreira, L. G., & Andricopulo, A. D. (2018). Practices in molecular docking and structure based virtual screening. Methods in fMolecular Biology, 1762, 31-50.
Elkamhawy, A., Ali, E. M. H., & Lee, K. (2021). New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011-2021) focussing on structure-activity relationship (SAR) and docking insights. Journal of enzyme inhibition and medicinal chemistry, 36(1), 1574–1602.
Global Cancer Observatory. (2021). Indonesia. International Agency for Research on Cancer, France.
Kalontong, P. K., Safithri, M., & Tarman, K. (2022). Penambatan Molekul Senyawa Aktif Spirulina platensis sebagai Inhibitor TMPRSS2 untuk Mencegah Infeksi SARS-COV-2. Jurnal Pengolahan Hasil Perikanan Indonesia, 25(2), 253-267.
Karami, T. K., Hailu, S., Feng, S., Graham, R., & Gukasyan, H. J. (2022). Eyes on Lipinski's Rule of Five: A New "Rule of Thumb" for Physicochemical Design Space of Ophthalmic Drugs. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 38(1), 43–55.
Kang, Y. J., Park, K. K., Chung, W. Y., Hwang, J. K., & Lee, S. K. (2009). Xanthorrhizol, a natural sesquiterpenoid, induces apoptosis and growth arrest in HCT116 human colon cancer cells. Journal of Pharmacological Sciences, 111(3):276–84.
Krihariyani, D., Sasongkowati, R., Haryanto, E. (2020). Studi In Silico Sifat Farmakokinetik, Toksisitas, dan Aktivitas Imunomodulator Brazilein Kayu Secang Terhadap Enzim 3-Chymotrypsin-Like Cysteine Protease Coronavirus. Journal of Indonesian Medical Laboratory and Science, Vol 1(1):76-90.
Kustina, E., & Zulharmita, M. S. (2020). Traditional uses, phytochemistry and pharmacology of Curcuma xanthorrhiza Roxb.: a review. Intl J Health Sci Res, 5(3), 2455-7587.
Maharani, D. S., et al. (2024). Identifikasi Senyawa Aktif Rimpang Kunyit (Curcuma longa L.) sebagai Kandidat Antikanker Melalui Studi In Silico terhadap Reseptor Lymphocyte-Specific Protein Tyrosine Kinase. Chimica et Natura Acta, Vol 12(1):49-57.
Manzano, SE., Garrido-Cardenas, J. A., & Manzano-Agugliaro, F. (2020). Worldwide research trends on medicinal plants. International journal of environmental research and public health, 17(10), 3376.
Mardianingrum, R., Bachtiar, K. R., Susanti, S., Aas Nuraisah, A. N., & Ruswanto, R. (2021). Studi In Silico Senyawa 1,4-Naphthalenedione-2-Ethyl-3-Hydroxy sebagai Antiinflamasidan Antikanker Payudara. Jurnal Penelitian Kimia, 17(1), 83–95
Ma’arif and T. Arifin. (2017). Optimasi Fitur Menggunakan Backward Elimination Dan Algoritma SVM Untuk Klasifikasi Kanker Payudara. J. Inform. 4(1) : 46–53.
Rachmatan, D. S., & Hidayat, T. (2020). Screening Tumbuhan Alternatif Penghasil Xanthorrhizol Menggunakan Pendekatan In-Silico Berdasarkan Marker MatK. Majalah Ilmiah Biologi BIOSFERA: A Scientific Journal, 37(1), 7-12.
Rahmawaty, A., Cahyani, F.R., Safitri, N., Sitepu, A.A.N.C., Hapitria, E.N. & Megantara, S. (2022). Uji in silico kandungan senyawa tanaman anggur (Vitis vinifera L.) untuk kandidat obat anti hiperlipidemia. Majalah Farmasi dan Farmakologi. 26(2): 57-62
Reynaldi, M. A., Faradilla, A., Nurbaeti, S. N., Haryanto., Fajrianty. 2023. Molecular Docking Senyawa Pada Komposisi Cincalok Terhadap Reseptor Plasmodium Falciparum Dihydroorotase Dehydrogenase. J-POP-Journal Pharmacy of Tanjungpura. 1(1), 1-3
Richa, M., Herlina, T. and Unang, S. (2015). Isolasi dan Molecular Docking Senyawa 6,7-Dihidro-17-Hidroksierisotrin dari Daun Dadap Belendung (Erythrina poeppigiana) Terhadap Aktivitas Sitotoksik Antikanker Payudara MCF-7, (Egfr 2), pp. 90–93.
Rompis, A. Y., & Nyoman, A. D. N. (2020). Aspek Genetik Kanker Kolorektal. Jurnal Sains dan Kesehatan, 2(3), 236-245
Sahoo, A., Jena, S., Ray, A., Dash, K. T., Nayak, S., & Panda, P. C. (2021). Chemical constituent analysis and antioxidant activity of leaf essential oil of Curcuma xanthorrhiza. Journal of Essential Oil Bearing Plants, 24(4), 736-744.
Singh, P. K., Kashyap, A., & Silakari, O. (2018). Exploration of the therapeutic aspects of Lck: A kinase target in inflammatory mediated pathological conditions. Biomedicine & Pharmacotherapy, 108, 1565-1571.
Salleh, N., Ismail, S., & Halim, M. 2016. Pengaruh Ekstrak Curcuma xanthorrhiza dan Konstituennya terhadap Aktivitas Enzin Metabolisme Obat Fase II. Pharmacognosy Research. 8(4) : 309-315
Vargas, J.A.R. et al. (2018). Molecular docking study on the interaction between 2-substituted-4,5-difuryl Imidazoles with different protein target for antileishmanial activity, Journal of Applied Pharmaceutical Science, 8(3), pp. 14–22.
Wilapangga, A. (2023). Analisis Potensi Farmakokinetik dan Toksisitas Pada Curcumin (Curcuma xanthorrhiza) Sebagai Brightening Terhadap Reseptor Protein Tirosinase Secara in Silico. Indonesian Journal of Pharmaceutical Education, Vol 3(2);203-211.
Yasin, S. A., Azzahra, A., Ramadhan, N. E., & Mylanda, F. (2020). Studi Penambatan Molekuler dan Prediksi ADMET Senyawa Bioaktif Beberapa Jamu Indonesia Terhadap SARS-COV-2 Main Protease (Mpro). BIMFI, Vol 7(2):24-41
