Uji Aktivitas Senyawa Apigenin dan Turunannya terhadap Reseptor Beta-1 Adrenergik sebagai Antihipertensi secara In Silico

Viola Marillia, Bertha Rusdi, Taufik Muhammad Fakih

Abstract


ABSTRACT: Hypertension is a degenerative disease with high prevalence among elderly in Indonesia. Hypertension can be treated by compounds that block beta-1 adrenergic receptor. Apigenine, which is found in celery, could lower blood pressure in rats.  Its antihypertensive activity was estimated due to blocking beta-1 adrenergic receptors. In this in silico study, apigenin and its derivatives were docked on beta-1 adrenergic receptor with molecular docking method to specify their affinity to the receptor. In addition to that, the physicochemistry, pharmacophore and toxicity of the compounds were also determined. The study result showed that the lipophilicity molar refractivity, and molecular mass of apigenin, apigenin 7-O--D-glucopyranoside, apigenin 7-O-(6-O-acetyl--D-glucopyranoside, apigenin 7-O--D-glucuronide, 7-O-methyl-apigenin, 4-O-methyl-apigenin, apigenin-8-C-glucoside meet the criteria of Lipinski’s Rule of Five, which means all compounds would absorb and distribute well in the body.  The results of a molecular docking study revealed that  apigenin and its derivatives had good affinity on beta-1 adrenergic receptor. The compound that had the best affinity was apigenin 7-O-(6-O-acetyl--D-glucopyranoside with concentration inhibition of 0,04033  and binding energy of -10,09 kcal/mol. This study also identified benzene, alcohol, and heteroaromatic as pharmacophore groups of apigenin and its derivatives. Toxicity study showed that all compounds were in class III which means that at high concentrations the compound might exhibit toxicity.  However all compounds were neither carcinogenic nor mutagenic.

Keywords: Hypertension, Apigenine, Beta-1 Adrenergic

ABSTRAK: Hipertensi adalah salah satu penyakit degeneratif dengan prevalensi tinggi di Indonesia, terutama pada pasien dengan usia di atas 40 tahun . Terapi hipertensi dapat dilakukan dengan beberapa golongan obat. Salah satu target pengobatan hipertensi adalah reseptor beta-1 adrenergik. Apigenin adalah senyawa yang ditemukan pada seledri dan diketahui dapat menurunkan tekanan darah pada tikus jantan. Hal ini dikarenakan senyawa apigenin diduga memiliki aktivitas hipertensi dengan mekanisme memblok reseptor beta-1 adrenergik. Pada penelitian ini dilakukan pengujian senyawa apigenin dan turunannya terhadap reseptor beta-1 adrenergik dengan menggunakan metode penambatan molekuler secara in silico. Penelitian ini bertujuan untuk mengetahui parameter fisikokimia, afinitas, farmakofor dan toksisitas senyawa turunan apigenin terhadap reseptor beta-1 adrenergik secara in silico. Hasil penentuan parameter fisiko kimia menunjukan bahwa lipofilisitas dan berat molekul senyawa apigenin, apigenin 7-O-β-D-glucopyranoside, apigenin 7-O-(6-O-acetyl-β-D-glucopyranoside, apigenin 7-O-β-D-glucuronide, 7-O-methyl-apigenin, 4-O-methyl-apigenin, apigenin-8-C-glucoside memenuhi persyaratan Lipinski’s Rule of Five yang artinya senyawa ini memiliki kemampuan absorpsi yang baik. Hasil dari penambatan molekular yaitu seluruh senyawa turunan apigenin memiliki afinitas terhadap reseptor beta-1 adrenergik. Senyawa yang memiliki afinitas paling baik adalah senyawa apigenin 7-O-(6-O-acetyl-β-D-glucopyranoside dengan nilai energi bebas ikatan -10,09 kkal/mol dan konstanta inhibisi 0,04033 molar. Identifikasi gugus farmakofor dari senyawa uji dan ligan alami menunjukan gugus benzen, alkohol, dan heteroaromatik berperan sebagai gugus farmakofor. Data toksisitas yang diperoleh adalah seluruh senyawa uji termasuk ke dalam toksisitas kelas III yang artinya pada konsentrasi yang tinggi tidak dijamin keamanan dalam penggunaannya. Kemudian seluruh senyawa uji tidak bersifat karsinogenik maupun mutagenik.

Kata Kunci: Hipertensi, Apigenin, Beta-1 Adrenergik


Keywords


Hipertensi, Apigenin, Beta-1 Adrenergik

Full Text:

PDF

References


Alhayek, S. and Preuss, C. (2020) Beta 1 Receptors. Stat Pearls. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532904/.

Ali, F. et al. (2017) ‘Health functionality of apigenin: A review’, International Journal of Food Properties, 20(6), pp. 1197–1238. doi: 10.1080/10942912.2016.1207188.

Barret, R. (2018) ‘Lipinski’s Rule of Five’, Therapeutical Chemistry.

Benigni, R. et al. (2008) ‘The Benigni / Bossa rulebase for mutagenicity and carcinogenicity – a module of Toxtree’, Health San Francisco, (May 2014). Available at: http://ihcp.jrc.ec.europa.eu/our_labs/computational_toxicology/doc/EUR_23241_EN.pdf.

Bristow (2000) ‘Mechanistic and Clinical Rationales for Using Beta-Blockers in Heart Failure’, J Card Fail, 6, pp. 8–14.

Darusman, F. and Fakih, T. M. (2020) ‘Studi Interaksi Senyawa Turunan Saponin dari Daun Bidara Arab (Ziziphus spina-christi L.) sebagai Antiseptik Alami secara In Silico’, Jurnal Sains Farmasi & Klinis, 7(3), p. 233. doi: 10.25077/jsfk.7.3.233-239.2020.

Engelhardt et al. (2002) ‘Inhibition of Na(+)-H(+) Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in Beta(1)-Adrenergic Receptor Transgenic Mice’, Circ Res, 90(814), p. 9.

Fan, J., Fu, A. and Zhang, L. (2019) ‘Progress in molecular docking’, Quantitative Biology, 7(2), pp. 83–89. doi: 10.1007/s40484-019-0172-y.

Frishman, W. H. (2016) ‘Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well’, Progress in Cardiovascular Diseases, 59(3), pp. 247–252. doi: 10.1016/j.pcad.2016.10.005.

Fu, C. et al. (2008) ‘Association of Beta (1)-Adrenergic Receptor Gene Polymorphisms with Left Ventricular Hypertrophy in Human Essential Hypertension’, Clinical Biochemistry, 41(10–11), pp. 773–778. doi: doi:10.1016/j.clinbiochem.2008.02.002.

Ganesan, K. and Xu, B. (2018) ‘A critical review on phytochemical profile and health promoting effects of mung bean (Vigna radiata)’, Food Science and Human Wellness, 7(1), pp. 11–33. doi: 10.1016/j.fshw.2017.11.002.

Giles, T. D. et al. (2009) ‘Definition and classification of hypertension: An update’, Journal of Clinical Hypertension, 11(11), pp. 611–614. doi: 10.1111/j.1751-7176.2009.00179.x.

Ginwala, R. et al. (2019) ‘Potential role of flavonoids in treating chronic inflammatory diseases with a special focus on the anti-inflammatory activity of apigenin’, Antioxidants, 8(2), pp. 1–30. doi: 10.3390/antiox8020035.

Gunardi et al. (2009) ‘Metode RPTLC dan Optimasi Fase Gerak Dalam Penetapan Harga Rm Sebagai Salah Satu Parameter Lipofilisitas Dalam Rancangan Obat’, Pemberian Cairan Karbohidrat Elektrolit, Status Hidrasi dan Kelelahan pada Pekerja Wanita, 43, pp. 254–259.

Gupta, P. et al. (2007) ‘Constituents of Ocimum sanctum with antistress activity’, Journal of Natural Products, 70(9), pp. 1410–1416. doi: 10.1021/np0700164.

Hostetler, G. L., Ralston, R. A. and Scwartz, S. J. (2017) ‘Flavones: Food Sources, Bioavaiability, Metabolism, and Bioactivity’, Adv. Nutr., 8, pp. 423–435.

John and Nancy (2005) Senyawa-Senyawa Sntihipertensi dan Terapi Obat Hipertensi dalam Goodman and Gilman, Editor. The Pharmacological Basis and Therapeutics. Jakarta: EGC.

Kahl, G. (2015) ‘Molecular docking’, The Dictionary of Genomics, Transcriptomics and Proteomics, 443, pp. 1–1. doi: 10.1002/9783527678679.dg07851.

Lauralee (2014) Fisiologi Manusia dari Sel ke Sistem. 8th edn. Jakarta: EGC.

Lee, H. et al. (2015) ‘Biosynthesis of Two Flavones, Apigenin and Genkwanin, in Escherichia coli’, J. Microbiol Biotechnocol, 25, pp. 1442–1448.

Leksana, E. (2011) ‘Pengelolaan Hemodinamik’, Jurnal CDK 188 Volume 38 Nomer 7. Bagian Anestesi dan Terapi Intensif RSUP dr. Kariadi/ Fakultas Kedokteran Universitas Diponegoro Semarang, Indonesia, 38(7), pp. 537–540. Available at: http://www.kalbemed.com/.

Lipinski, C. et al. (1997) ‘Experimental and Computational Approches to Estimate Solubility and Permeability in Drug Discovery and Development Settings’, Adv. Drug Deliv, 23.

Longo, D. et al. (2011) Horrison’s Principles of Internal Medicine. 18th edn. New York: Mc. Graw Hill.

Mahajan, N. et al. (2013) ‘A phytopharmacological overview on Ocimum species with special emphasis on Ocimum sanctum’, Biomedicine and Preventive Nutrition, 3(2), pp. 185–192. doi: 10.1016/j.bionut.2012.08.002.

Meng, X.-Y. et al. (2012) ‘Molecular Docking: A Powerful Approach for Structure-Based Drug Discovery’, Current Computer Aided-Drug Design, 7(2), pp. 146–157. doi: 10.2174/157340911795677602.

Naqiyya, N. (2020) ‘Potensi Seledri (Apium Graveolens L.) Sebagai Antihipertensi’, Jurnal Stikes, 2(2), pp. 160–166.

Nessa et al. (2018) ‘Uji Efek Antihipertensi Ekstrak Etanol Daun Seledri (Apium gravolens L.) Pada Tikus Putih Jantan Diindiksi Pednison dan NaCl’, Jurnal Akademi Farmasi Prayoga, 3(1), pp. 1–9.

Pagadala, N. S., Syed, K. and Tuszynski, J. (2017) ‘Software for molecular docking: a review’, Biophysical Reviews, 9(2), pp. 91–102. doi: 10.1007/s12551-016-0247-1.

Patlewicz, G. et al. (2008) ‘An evaluation of the implementation of the Cramer classification scheme in the Toxtree software’, SAR and QSAR in Environmental Research, 19(5–6), pp. 495–524. doi: 10.1080/10629360802083871.

Peng, X. et al. (2008) ‘Inhibitory effect of mung bean extract and its constituents vitexin and isovitexin on the formation of advanced glycation endproducts’, Food Chemistry, 106(2), pp. 475–481. doi: 10.1016/j.foodchem.2007.06.016.

PERKI, P. D. S. K. I. (2015) Pedoman Tatalaksana Hipertensi Pada Penyakit Kardiovaskular. Pertama. Jakarta: PERKI Indonesian Heart Association.

Pham, L. L., Borghoff, S. J. and Thompson, C. M. (2020) ‘Comparison of threshold of toxicological concern (TTC) values to oral reference dose (RfD) values’, Regulatory Toxicology and Pharmacology, 113(October 2019). doi: 10.1016/j.yrtph.2020.104651.

Pollastri, M. P. (2010) ‘Overview on the rule of five’, Current Protocols in Pharmacology, (SUPPL. 49), pp. 1–8. doi: 10.1002/0471141755.ph0912s49.

Riskesdas, K. (2018) ‘Hasil Utama Riset Kesehata Dasar (RISKESDAS)’, Journal of Physics A: Mathematical and Theoretical, 44(8), pp. 1–200. doi: 10.1088/1751-8113/44/8/085201.

Salehi, B. et al. (2019) ‘The therapeutic potential of Apigenin’, International Journal of Molecular Sciences, 20(6). doi: 10.3390/ijms20061305.

Saputra, O. and Fitria, T. (2016) ‘Khasiat Daun Seledri ( Apium graveolens ) Terhadap Tekanan Darah Tinggi Pada Pasien Hiperkolestrolemia’, Majority, 5(April), pp. 1–6.

Setiati, S., Alwi, I., Sudoyo A. W., Simadibrata, M. (2017) Buku Ajar Ilmu Penyakit Dalam. Jakarta: Interna Publishing.

Shukla, S. and Gupta, S. (2010) ‘Apigenin: A promising molecule for cancer prevention’, Pharmaceutical Research, 27(6), pp. 962–978. doi: 10.1007/s11095-010-0089-7.

Smeltzer, B. (2008) Medical Surgical Nursing. Philadelphia: Lippincott William & Wilkins.

Staessen, J. A. et al. (2003) ‘Essential hypertension’, Lancet, 361(9369), pp. 1629–1641. doi: 10.1016/S0140-6736(03)13302-8.

Tedjasukmana, P. (2012) ‘Tata Laksana Hipertensi’, CDK-192, 39(4), pp. 251–255.

Thomsen, R. and Christensen, M. (2006) ‘MolDock: A New Technique for High-Accuracy Molecular Docking’, J. Med. Chem, 49, pp. 3315–3321.

Warne, T. et al. (2008) ‘Structure of a β1-adrenergic G-protein-coupled receptor’, Nature, 454(7203), pp. 486–491. doi: 10.1038/nature07101.

Yan, J. et al. (2014) ‘Apigenin Accumulation and Expression Analysis of Apigenin Biosynthesis Relative Genes in Celery’, Scientia Horticulturae, 165, pp. 218–224.

Yulanda, G. and Lisiswanti, R. (2017) ‘Penatalaksanaan Hipertensi Primer’, Majority, 6(1), pp. 25–33.

Zhang, M. Q. and Wilkinson, B. (2007) ‘Drug discovery beyond the “rule-of-fiveâ€â€™, Current Opinion in Biotechnology, 18(6), pp. 478–488. doi: 10.1016/j.copbio.2007.10.005.

Nuraeni Anisa Dwi, Lukmayani Yani, Kodir Reza Abdul. (2021). Uji Aktivitas Antibakteri Propionibacterium acnes Ekstrak Etanol dan Fraksi Daun Karuk (Piper sarmetosum Roxb. Ex. Hunter) serta Analisis KLT Bioautografi. Jurnal Riset Farmasi, 1(1), 9-15.




DOI: http://dx.doi.org/10.29313/.v0i0.29329

Flag Counter