PREDIKSI TOKSISITAS, ANALISIS ADME DAN DOCKING MOLEKULER ASIATICOSIDE TERHADAP PENGHAMBATAN ANGIOTENSIN CONVERTING ENZYME
TOXICITY PREDICTION, ADME ANALYSIS AND MOLECULAR DOCKING OF ASIATICOSIDE AGAINST ANGIOTENSIN CONVERTING ENZYME INHIBITION
DOI:
https://doi.org/10.37090/jfl.v14i1.2411Abstract
The presence of risk factors related to the severity of cardiovascular disease is a key consideration in adjunct therapy as an immunostimulant.One of the plants with potential as a cardioprotective immunostimulant is pegagan.Asiaticoside in pegagan leaves can inhibit AT1R and reduce NF-κβ activity.This study aims to predict the interaction of ligands with the receptor of cardioprotective immunostimulant agents.This study uses Molecular Docking simulations with molecular docking using Autodock Tools 1.5.6 and visualization using BIOVIA Discovery Studio Visualizer 24.1.The target macromolecule used is AT1R (PDB 4ZUD) which was downloaded from the PDB.The molecular docking parameters were analyzed based on binding energy.Pharmacokinetic characteristics were evaluated using the SwissADME tool.The binding result of the test ligand molecule to AT1R is -4.50 ±0.595 kcal/mol. The reference ligand has an AT1R binding value of -7.74±0.036 kcal/mol. Validation of the molecular docking method has an RMSD value of 1.857±0.356 Å. The toxicity prediction of the compound Asiatikoside at LD50 4000mg/kg and pharmacokinetic analysis were conducted using the boiled-egg method, which indicates that Asiatikoside is predicted cannot cross the blood-brain barrier. The ADME prediction results show that the Asiatikoside has 3 parameters that do not meet the bioavailability parameters, namely a molecular weight of 959.12g/mol, TPSA polarity of 315.21A, and flexibility of 10. Conclusion Asiaticosides is predicted to have limitations in terms of oral bioavailability, so special formulations such as nanoencapsulation techniques are needed to help improve its bioavailability
Keywords: Asiaticosides; ACE Inhibition; Molecular Docking
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References
[1] F. D. Fuchs and P. K. Whelton, “High Blood Pressure and Cardiovascular Disease,” Hypertension, vol. 75, no. 2, pp. 285–292, 2020, doi: 10.1161/Hypertensionaha.119.14240.
[2] F. D. Marques et al., “Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats,” Int. J. Hypertens., vol. 2012, 2012, doi: 10.1155/2012/795452.
[3] B. Sun et al., “Therapeutic Potential of Centella asiatica and Its Triterpenes : A Review,” Front. Pharmacol., vol. 11, no. September, pp. 1–24, 2020, doi: 10.3389/fphar.2020.568032.
[4] M. K. Ames, C. E. Atkins, and B. Pitt, “The renin-angiotensin-aldosterone system and its suppression,” J. Vet. Intern. Med., vol. 33, no. 2, pp. 363–382, 2019, doi: 10.1111/jvim.15454.
[5] P. Niu et al., “Effect of intrarenal renin-angiotensin-aldosterone system on renal function in patients after cardiac surgery.,” Medicine (Baltimore)., vol. 101, no. 7, p. e28854, Feb. 2022, doi: 10.1097/MD.0000000000028854.
[6] M. K. Bunaim, Y. Kamisah, M. N. Mohd Mustazil, J. S. Fadhlullah Zuhair, A. H. Juliana, and N. Muhammad, “Centella asiatica (L.) Urb. Prevents Hypertension and Protects the Heart in Chronic Nitric Oxide Deficiency Rat Model,” Front. Pharmacol., vol. 12, no. December, pp. 1–12, 2021, doi: 10.3389/fphar.2021.742562.
[7] F. Sulistiawati and M. Radji, “Potensi Pemanfaatan Nigella sativa L. sebagai Imunomodulator dan Antiinflamasi,” Pharm. Sci. Res., vol. 1, no. 2, pp. 65–77, 2014, doi: 10.7454/psr.v1i2.3493.
[8] I. M. R. Islami, “Literatur Review: Pemberian Pegagan (Centella Asiatica) Sebagai Minuman Alternatif Untuk Menurukan Tekanan Darah Pada Lansia,” J. Keperawatan Prof., vol. 11, no. 1, pp. 201–2017, 2023, doi: 10.33650/jkp.v11i1.6204.
[9] J. H. Park, Y. H. Seo, J. H. Jang, C. H. Jeong, S. Lee, and B. Park, “Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway,” J. Neuroinflammation, vol. 14, no. 1, pp. 1–15, 2017, doi: 10.1186/s12974-017-1009-0.
[10] N. L. A. Dewi, “Pemisahan, Isolasi, dan Identifikasi Senyawa Saponin Dari Herba Pegagan (Centella asiatica L. Urban),” J. Farm. Udayana, vol. 7, no. 2, p. 68, 2018, doi: 10.24843/jfu.2018.v07.i02.p05.
[11] N. N. M. Razali, C. T. Ng, and L. Y. Fong, “Cardiovascular Protective Effects of Centella asiatica and Its Triterpenes: A Review,” Planta Med., vol. 85, no. 16, pp. 1203–1215, 2019, doi: 10.1055/a-1008-6138.
[12] Aradila irsalina, “Efek Daun Pegagan (C. Asiatica) Sebagai Neuroprotektor,” NBER Work. Pap., vol. 5, p. 89, 2013, [Online]. Available: http://www.nber.org/papers/w16019
[13] H. Zhang et al., “Structural basis for ligand recognition and functional selectivity at angiotensin receptor,” J. Biol. Chem., vol. 290, no. 49, pp. 29127–29139, 2015, doi: 10.1074/jbc.M115.689000.
[14] P. W. Rose et al., “The RCSB Protein Data Bank: Views of structural biology for basic and applied research and education,” Nucleic Acids Res., vol. 43, no. D1, pp. D345–D356, 2015, doi: 10.1093/nar/gku1214.
[15] G. S. Prasad, G. S. Kumar, and K. Srisailam, “Novel metabolites of losartan as human peroxisome proliferator activated receptor gamma (PPARγ) and human angiotensin receptor (AT1R) binders: an in silico study,” Int. J. Pharm. Biol. Sci., vol. 8, no. 2, pp. 330–337, 2018.
[16] Ruswanto, Siswandono, M. Richa, N. Tita, and L. Tresna, “Molecular docking of 1-benzoyl-3-methylthiourea as anti cancer candidate and its absorption, distribution, and toxicity prediction,” J. Pharm. Sci. Res., vol. 9, no. 5, pp. 680–684, 2017.
[17] O. Nursanti, “Prediksi Toksisitas dan Farmakokinetika untuk mendapatkan Kandidat Obat Antidiabetes,” J. Pharm. care Sci., vol. 3, no. 1, p. 34, 2023, doi: 10.52365/jond.v3i1.654.
[18] R. R. R. Bahi, R. Herowati, and N. Harmastuti, “Studi Biokemoinformatika Kandungan Kimia Daun Sambiloto (Andrographis paniculata (Burm.f.) Nees) sebagai Antihiperglikemia serta Prediksi Parameter Farmakokinetik dan Toksisitas,” Pharm. J. Farm. Indones. (Pharmaceutical J. Indones., vol. 17, no. 2, p. 466, 2020, doi: 10.30595/pharmacy.v17i2.8944.
[19] S. Ferwadi, G. Rahmat, and W. Astuti, “Molecular Docking Study of Cinnamate Acid Compound and its Derivatives as Protein 1J4X Inhibitor to Cervical Cancer Cell,” J. Kim. Mulawarman, vol. 14, no. 2, pp. 84–90, 2017, [Online]. Available: http://www.rcsb.org/pdb/explore/explore.do?
[20] A. B. Pratama, R. Herowati, H. M. Ansory, F. Farmasi, and U. S. Budi, “Studi Docking Molekuler Senyawa Dalam Minyak Atsiri Pala ( Myristica fragrans H .) Dan Senyawa Turunan Miristisin Terhadap Target Terapi Kanker Kulit,” Maj. Fasmaseutik, vol. 17, no. 2, pp. 233–242, 2021, doi: 10.22146/farmaseutik.v17i2.59297.
[21] E. Y. Sukandar and S. H. Sheba, “Acute and Sub-chronic Toxicity Studies of Combination of Physalis angulata L . ( Cecendet ) Extract and Methylprednisolone on Animals,” Int. J. Integr. Heal. Sci., vol. 7, no. 1, pp. 48–55, 2019, doi: ; http://doi.org/10.15850/ijihs.v7n1.1619.
[22] A. Daina, O. Michielin, and V. Zoete, “SwissADME : a free web tool to evaluate pharmacokinetics , drug- likeness and medicinal chemistry friendliness of small molecules,” Nat. Publ. Gr., no. March, pp. 1–13, 2017, doi: 10.1038/srep42717.
[23] K. Z. Deviana, “Analisis Penambatan Molekuler dan Prediksi Toksisitas dan ADME Penghambat Enzim Dipeptidil Peptidase IV dari Senyawa Aktif Momordica charantia L . sebagai Antidiabetes Analysis of Molecular Docking and Prediction of Toxicity and ADME of Dipeptidyl Peptida,” Phaemaceutical J. Indones., vol. 18, no. 02, pp. 361–370, 2021.
[24] S. Shakil, “Original article : A Simple Click By Click Protocol To Perform Docking :,” EXCLI J., vol. 12, pp. 831–857, 2013.
[25] Kolina Jennifer, “Mode Ikatan Metabolit Sekunder di Tanaman Akar Kuning (Arcangelisia flava L.) dengan Nitrat Oksida Sintase,” Fitofarmaka J. Ilm. Farm., vol. 8, no. 1, pp. 50–58, 2018.
[26] R. Rollando, C. Mycolic, and A. Synthase, “Pendekatan Struktur Aktivitas dan Penambatan Molekul Senyawa 2-iminoethyl 2-(2-(1- hydroxypentan-2-yl) phenyl)acetate Hasil Isolasi Fungi Endofit Genus Fusarium sp pada Enzim β-ketoasil-ACP KasA Sintase dan Enzim Asam Mikolat Siklopropana Sintase,” Pharm. J. Indones., vol. 3, no. 2, pp. 45–51, 2018.
[27] C. R. Girija, P. Karunakar, C. S. Poojari, N. S. Begum, and A. A. Syed, “Molecular Docking Studies of Curcumin Derivatives with Multiple Protein Targets for Procarcinogen Activating Enzyme Inhibition,” J. Proteomic Bioinforma., vol. 3, no. 6, pp. 200–203, 2010, doi: 10.4172/jpb.1000140.
[28] A. Hernández-santoyo, A. Y. Tenorio-barajas, V. Altuzar, H. Vivanco-cid, and C. Mendoza-barrera, “Protein-Protein and Protein-Ligand Docking,” Protein Eng. - Technol. Apl., no. Figure 1, 2013, doi: 10.5772/56376.
[29] M. Umamaheswari, A. Madeswaran, and K. Asokkumar, “Virtual Screening Analysis and In-vitro Xanthine Oxidase Inhibitory Activity of Some Commercially Available Flavonoids,” Iran. J. Pharm. Res., vol. 12, no. NOvember 2011, pp. 317–323, 2013.
[30] H. Zhang et al., “Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor*♦,” J. Biol. Chem., vol. 290, no. 49, pp. 29127–29139, 2015, doi: https://doi.org/10.1074/jbc.M115.689000.
[31] D. T. Infield, A. Rasouli, G. D. Galles, C. Chipot, and C. A. Ahern, “Cation-π interactions and their functional roles in membrane proteins,” jounral Mol. Biol., vol. 433, no. 17, 2021, doi: 10.1016/j.jmb.2021.167035.Cation-.
[32] M. J. A. Bernaldez and J. B. Billones, “In Silico Analysis of Binding Interactions between GSK983,” AIP Conf. Proc., pp. 020073–1–020073–8, 2018.
