Studi In Silico Senyawa dalam Daun Kelor (Moringa oleifera L.) sebagai Inhibitor Protein Kinase C Alpha pada Kanker Payudara
Abstrak
Kanker payudara merupakan salah satu jenis tumor ganas yang timbul akibat meningkatnya pertumbuhan sel secara abnormal pada epitel duktus maupun lobulus di jaringan payudara. Migrasi sel kanker payudara dapat diinisiasi oleh meningkatnya ekspresi protein kinase C alpha sehingga menginduksi terjadinya potensi invasif sel kanker payudara dan menyebabkan metastasis. Senyawa Fenolik dalam daun kelor (Moringa oleifera) berpotensi untuk menginduksi apoptosis dengan menghambat jalur pensinyalan yang diinisiasi oleh protein kinase C alpha. Tujuan dari penelitian ini untuk mengetahui mekanisme inhibisi pada protein kinase alpha dari senyawa yang terkandung di dalam daun kelor (Moringa oleifera) secara in silico menggunakan simulasi penambatan molekuler. Tahapan penelitian terdiri atas preparasi dan optimasi protein kinase C alpha serta senyawa uji, validasi metode dan simulasi penambatan molekuler melalui program AutoDockTools 1.5.6, pemodelan farmakofor melalui program LigandScout, serta prediksi profil farmakokinetika dan ADMET berdasarkan parameter Lipinski’s Rule of Five melalui situs pre-ADMET. Hasil dari simulasi penambatan molekuler tersebut kemudian divisualisasikan melalui program BIOVIA Discovery Studio 2020 Client. Dari hasil simulasi penambatan molekuler diperoleh 3 senyawa yang memiliki nilai binding energy paling rendah dan konstanta inhibisi paling kecil yaitu myricetin (∆G = -8,49 kcal/mol; Ki = 600,42 nM), kuersetin (∆G = -7,94 kcal/mol; Ki = 1,52 uM), dan kaempferol (∆G = -7,75 kcal/mol; Ki = 2,08uM). Namun, hanya kaempferol yang memiliki sifat absorpsi pada usus serta permeabilitas yang lebih baik dibandingkan dengan myricetin dan kuersetin. Oleh karena itu, pada penelitian ini menunjukkan bahwa senyawa kaempferol berpotensi untuk dijadikan senyawa kandidat sebagai obat antikanker payudara melalui mekanisme inhibisi protein kinase C alpha.
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Hero SK. Faktor Risiko Kanker Payudara. J Med Hutama. 2021 Oct 4;3(1):1533–7.
International Agency for Research on Cancer (IARC). Indonesia - Global Cancer Observatory. https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets.pdf. 2020.
American Cancer Society. Breast Cancer Treatment Guideline. Atlanta: American Cancer Society; 2017.
Iqmy LO, Setiawati S, Yanti DE. Faktor Risiko yang Berhubungan dengan Kanker Payudara. J Kebidanan Malahayati. 2021 Jan 31;7(1):32–6.
Nurrohmah A, Aprianti A, Hartutik S. Risk Factors of Breast Cancer. Gaster. 2022 Feb 8;20(1):1.
Tor YS, Yazan LS, Foo JB, Wibowo A, Ismail N, Cheah YK, et al. Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile. PLoS One. 2015 Jun 5;10(6):e0127441.
Jan R, Chaudhry G e S. Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics. Adv Pharm Bull. 2019 Jun 1;9(2):205–18.
Nurmaulawati R, Purwidyaningrum I, Indrayati A. Kajian Literatur Uji Aktivitas Antikanker Payudara Tanaman Ranti (Solanum nigrum Linn.) Secara in vitro dan in vivo. Pharm Med J. 2021;4(2):44–53.
Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. Targeting cancer with kinase inhibitors. J Clin Invest. 2015 May 1;125(5):1780–9.
Meiyanto E. Biologi Molekuler. Yogyakarta: Universitas Gadjah Mada; 2002.
Yance D. A Novel Approach to Cancer Treatment. New York: McGraw-Hill Education; 2005. 15 p.
Hamid IS, Aksono EB, Sukmanadi M, Purnama MTE. Antiangiogenesis activity test of tin leaf (Ficus carica L.) on the number of blood vessels and VEGF expression of chorioallantoic membrane of embryonated chicken eggs. Eur J Oncol Pharm. 2018 Oct;1(4):e00007.
Lønne GK, Cornmark L, Zahirovic IO, Landberg G, Jirström K, Larsson C. PKCα expression is a marker for breast cancer aggressiveness. Mol Cancer. 2010 Dec 14;9(1):76.
Cameron AJ, Procyk KJ, Leitges M, Parker PJ. PKC alpha protein but not kinase activity is critical for glioma cell proliferation and survival. Int J Cancer. 2008 Aug 15;123(4):769–79.
Haughian JM, Reno EM, Thorne AM, Bradford AP. Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis. Int J Cancer. 2009 Dec 1;125(11):2556–64.
Nakagawa S, Fujii T, Yokoyama G, Kazanietz MG, Yamana H, Shirouzu K. Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: Involvement of protein kinase C? and extracellular signal-regulated kinase mitogen-activated protein kinase. Mol Carcinog. 2003 Nov;38(3):106–16.
Stewart JR, O’Brian CA. Resveratrol Antagonizes EGFR-Dependent Erk1/2 Activation in Human Androgen-Independent Prostate Cancer Cells with Associated Isozyme-Selective PKCα Inhibition. Invest New Drugs. 2004 Apr;22(2):107–17.
Leone A, Spada A, Battezzati A, Schiraldi A, Aristil J, Bertoli S. Cultivation, Genetic, Ethnopharmacology, Phytochemistry and Pharmacology of Moringa oleifera Leaves: An Overview. Int J Mol Sci. 2015 Jun 5;16(12):12791–835.
Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM, et al. Improved Survival with Bevacizumab in Advanced Cervical Cancer. N Engl J Med. 2014 Feb 20;370(8):734–43.
Sreelatha S, Jeyachitra A, Padma PR. Antiproliferation and induction of apoptosis by Moringa oleifera leaf extract on human cancer cells. Food Chem Toxicol. 2011 Jun;49(6):1270–5.
Chumark P, Khunawat P, Sanvarinda Y, Phornchirasilp S, Morales NP, Phivthong-ngam L, et al. The in vitro and ex vivo antioxidant properties, hypolipidaemic and antiatherosclerotic activities of water extract of Moringa oleifera Lam. leaves. J Ethnopharmacol. 2008 Mar;116(3):439–46.
Banji OJF, Banji D, Kavitha R. Immunomodulatory effects of alcbholic and hydroalcoholic extracts of Moringa olifera Lam leaves. Indian J Exp Biol. 2012 Apr;50(4):270–6.
Chen AY, Chen YC. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013 Jun;138(4):2099–107.
Pinzi L, Rastelli G. Molecular Docking: Shifting Paradigms in Drug Discovery. Int J Mol Sci. 2019 Sep 4;20(18):4331.
Zhao J, Cao Y, Zhang L. Exploring the computational methods for protein-ligand binding site prediction. Comput Struct Biotechnol J [Internet]. 2020;18:417–26. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2001037019304465
Muttaqin FZ. MOLECULAR DOCKING AND MOLECULAR DYNAMIC STUDIES OF STILBENE DERIVATIVE COMPOUNDS AS SIRTUIN-3 (SIRT3) HISTONE DEACETYLASE INHIBITOR ON MELANOMA SKIN CANCER AND THEIR TOXICITIES PREDICTION. J Pharmacopolium [Internet]. 2019 Aug 31;2(2). Available from: https://ejurnal.stikes-bth.ac.id/index.php/P3M_JoP/article/view/489
Du X, Li Y, Xia YL, Ai SM, Liang J, Sang P, et al. Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods. Int J Mol Sci [Internet]. 2016 Jan 26;17(2):144. Available from: http://www.mdpi.com/1422-0067/17/2/144
Torres PHM, Sodero ACR, Jofily P, Silva-Jr FP. Key Topics in Molecular Docking for Drug Design. Int J Mol Sci [Internet]. 2019 Sep 15;20(18):4574. Available from: https://www.mdpi.com/1422-0067/20/18/4574
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem [Internet]. 2009;NA-NA. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jcc.21334
Cartika H. Modul Cetak Bahan Ajar Farmasi Kimia Farmasi. Jakarta: Pusdik SDM Kesehatan; 2016.
Kreutzer AG, Hamza IL, Spencer RK, Nowick JS. X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an Aβ 17–36 β-Hairpin. J Am Chem Soc [Internet]. 2016 Apr 6;138(13):4634–42. Available from: https://pubs.acs.org/doi/10.1021/jacs.6b01332
Prasetiawati R, Suherman M, Permana B, Rahmawati R. Molecular Docking Study of Anthocyanidin Compounds Against Epidermal Growth Factor Receptor (EGFR) as Anti-Lung Cancer. Indones J Pharm Sci Technol. 2021 Feb;8(1):8.
Ravindranath PA, Forli S, Goodsell DS, Olson AJ, Sanner MF. AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility. Fetrow JS, editor. PLOS Comput Biol. 2015 Dec;11(12):e1004586.
Musoev A, Numonov S, You Z, Gao H. Discovery of Novel DPP-IV Inhibitors as Potential Candidates for the Treatment of Type 2 Diabetes mellitus Predicted by 3D QSAR Pharmacophore Models, Molecular Docking and de novo Evolution. Molecules. 2019 Aug;24(16).
Ferwadi S, Gunawan R, Astuti W. Studi Docking Molekular Senyawa Asam Sinamat Dan Derivatnya Sebagai Inhibitor Protein 1j4x Pada Sel Kanker Serviks. J Kim Mulawarman. 2017;14(2):84–90.
Agistia DD, Purnomo H, Tegar M, Nugroho AE. Interaction Between Active Compounds from Aegle marmelos correa as Anti inflammation Agent with COX-1 and COX-2 Receptor. Maj Obat Tradis. 2013;18(2):80–7.
Sun Z, Zhou D, Yang J, Zhang D. Doxorubicin promotes breast cancer cell migration and invasion via DCAF13. FEBS Open Bio [Internet]. 2022 Jan 5;12(1):221–30. Available from: https://onlinelibrary.wiley.com/doi/10.1002/2211-5463.13330
Pratama M. Studi Docking Molekular Senyawa Turunan Kuinolin terhadap Reseptor Estrogen-Α. J Surya Med. 2016;2(1):1–7.
Vargas JAR, Lopez AG, Piñol MC, Froeyen M. Molecular docking study on the interaction between 2-substituted-4,5-difuryl Imidazoles with different Protein Target for antileishmanial activity. J Appl Pharm Sci [Internet]. 2018;8(3):14–22. Available from: http://www.japsonline.com/abstract.php?article_id=2571
Dermawan D, Sumirtanurdin R, Dewantisari D. Molecular Dynamics Simulation of Estrogen Receptor Alpha Against Andrografolid as Anti Breast Cancer. Indones J Pharm Sci Technol. 2019;6(2):65–76.
Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004 Dec;1(4):337–41.
Gao Y, Gesenberg C, Zheng W. Oral Formulations for Preclinical Studies. In: Developing Solid Oral Dosage Forms [Internet]. Elsevier; 2017. p. 455–95. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128024478000170
Djajanti AD, Asfi D. UJI AKTIVITAS SEDIAAN KRIM EKSTRAK ETANOL HERBA SELEDRI (Apium graveolens L.) TERHADAP LUKA SAYAT PADA KELINCI (Oryctolagus cuniculus L.). Media Kesehat Politek Kesehat Makassar. 2018 Dec 31;13(2):40.
Shargel L, Yu A. Applied Biopharmaceutics and Pharmacokinetics. 7th ed. New York: McGraw Hill; 2016.
Wang NN, Dong J, Deng YH, Zhu MF, Wen M, Yao ZJ, et al. ADME Properties Evaluation in Drug Discovery: Prediction of Caco-2 Cell Permeability Using a Combination of NSGA-II and Boosting. J Chem Inf Model [Internet]. 2016 Apr 25;56(4):763–73. Available from: https://pubs.acs.org/doi/10.1021/acs.jcim.5b00642
Lindup WE, Orme MC. Clinical pharmacology: plasma protein binding of drugs. BMJ [Internet]. 1981 Jan 17;282(6259):212–4. Available from: https://www.bmj.com/lookup/doi/10.1136/bmj.282.6259.212
MA X lei, CHEN C, YANG J. Predictive model of blood-brain barrier penetration of organic compounds1. Acta Pharmacol Sin [Internet]. 2005 Apr;26(4):500–12. Available from: http://www.nature.com/doifinder/10.1111/j.1745-7254.2005.00068.x
Hero SK. Faktor Risiko Kanker Payudara. J Med Hutama. 2021 Oct 4;3(1):1533–7.
International Agency for Research on Cancer (IARC). Indonesia - Global Cancer Observatory. https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets.pdf. 2020.
DOI: https://doi.org/10.24198/ijbp.v3i3.46289
DOI (PDF): https://doi.org/10.24198/ijbp.v3i3.46289.g22258
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