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Abstract

The objective of the study was to generate a series of pharmacophores from a parent flavone skeleton and evaluate their in silico HMG CoA reductase and cholesterol esterase enzyme inhibitory potential using the software AutoDock 4.2. A total of eighteen flavonoid compounds were generated from flavone structure using the software ChemSketch. The docking studies were carried out for all these compounds using the software AutoDock4.2 with the enzymes HMG CoA reductase and cholesterol esterase. The docking parameters like binding energy, inhibition constant and intermolecular energy were determined. The results obtained were compared with the standard drugs. Rosuvastatin and simvastatin were used as the standards for HMG CoA reductase and cholesterol esterase inhibitory activity respectively. The binding sites of both enzymes for these ligands and their pharmacophores were identified. Based on the docking parameters for the enzyme HMG CoA reductase the binding energy, inhibition constant, intermolecular energy of Rosuvastatin was found to be -7.97 kcalmol-1, 1.44nm was and -11.85 kcalmol-1 respectively. The flavonoid compounds showed binding energy ranging between -11.85 to -9.09 to kcalmol-1, inhibition constant ranging from 2.06 nM to 216.45 nM intermolecular energy ranging between -13.94 kcalmol‑1 to -10.88 kcalmol‑1. Among the flavonoid compounds FA5 showed better binding energy -11.85 kcalmol-1, inhibition constant (2.06 nM) and intermolecular energy (-13.94 kcalmol‑1) when compared to the standard.The docking parameters of standard Simvastatin to cholesterol esterase exhibited a binding energy -6.72 kcalmol-1, inhibition constant (11.89 nm) and intermolecular energy -9.11 kcalmol-1. The flavonoid compounds showed binding energy ranging between -9.03 kcalmol-1 to -7.28 kcalmol-1, inhibition constant ranging from 241.43 nm to 4.71 μM, intermolecular energy ranging between -10.69 kcalmol-1 to -9.37 kcalmol-1. From the selected flavonoids FA12 had showed better binding energy (-9.03 kcal/mol), inhibition constant (241.43 nm), when compared to the standard simvastatin (-6.72 kcalmol-1). This proved that FA12 has the potential to inhibit cholesterol esterase. The compound FA2 exhibited better intermolecular energy -10.69 kcalmol1) when compared to the standard and the compound FA12. In conclusion, these results indicate that selected flavonoids, FA5 has better binding sites and interaction for the enzyme HMG CoA reductase  and FA12 have better binding sites and interactions with cholesterol esterase enzyme and can be synthesized and screened for their in vitro and in vivo potential.

Keywords

In silico Atherosclerosis, HMG CoA reductase cholesterol esterase AutoDock Flavonoids

Article Details

How to Cite
K. Asok Kumar, P. Jagannath, & Francis Saleshier. (2021). Computational and molecular designing studies of novel flavonoid analogues as HMG CoA Reductase and cholesterol esterase inhibitors for their Cardioprotective effect using in Silico docking studies. International Journal of Research in Pharmacology & Pharmacotherapeutics, 7(2), 166-177. https://doi.org/10.61096/ijrpp.v7.iss2.2018.166-177

References

  1. [1]. Rahmathulla SBM, Lakshmidevi K. Advanced molecular and cell based therapies for atherosclerosis. 2015. Asian J Pharm Clin Res 8(1), 2015, 54-9.
  2. [2]. Adaramoye OA, Akintayo O, Achem J, Fafunso MA. Lipid-lowering effects of methanolic extract of Vernonia amygdalina leaves in rats fed on high cholesterol diet. Vasc Health Risk Manag 4(1), 2008, 235–41.
  3. [3]. Gholamhoseinian A, Sharifi-Far F, Shahouzehi B. Inhibitory activity of some plant methanol extracts on 3-hydroxy-3-methylglutaryl coenzyme a reductase. Int J Pharmacol 6, 2010, 705–11.
  4. [4]. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels:The framingham study. JAMA 256(20), 1986, 2835-8.
  5. [5]. Hoekstra M. SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease. Atherosclerosis 258, 2017, 153-61.
  6. [6]. Friesen JA, Rodwell VW. The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol 5(11), 2004, 248.
  7. [7]. Wong WWL, Dimitroulakos MD, Minden MD and Penn L. HMG CoA reductase inhibitors and the malignant cell: The statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16, 2002, 508-519.
  8. [8]. Bochar Da, Brown RJ, Doolittle, Klenk HP and Lam W. 3-Hydroxy-3-Methylglutaryl coenzyme a reductase of sulfolobus solfataricus: DNA sequence, phylogeny, expression in escherichia coli of the hmga gene and purification and kinetic characterization of the gene product. J Bacteriol 179, 1997, 3632-8.
  9. [9]. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circula¬tion 101(2), 2000, 207–13.
  10. [10]. 10. Deng R. Food and food supplements with hypocholesterolemic effeects. Recent Patents Food Nutr Agric 1, 2009, 15-24.
  11. [11]. Hui DY, Howles PN. Molecular mechanisms of cholesterol absorption and transport in the intestine. Seminars Cell Dev Biol 16, 2005, 183-192.
  12. [12]. Wang CS, Hartsuck JA. Bile salt-activated lipase. A multiple function lipolytic enzyme. Biochim Biophys Acta 1166, 1993, 1–19.
  13. [13]. M. Pietsch, Gütschow M. Synthesis of tricyclic 1,3-oxazin-4-ones and kinetic analysis of cholesterol esterase and acetylcholinesterase inhibition, J Med Chem 48, 2005, 8270-88.
  14. [14]. Myers-Payne SC, Hui DY, Brockman HL, Schroeder F. Cholesterol esterase: A cholesterol transfer protein. Biochemistry 34, 1995, 3942–7.
  15. [15]. Pietsch, M., Gutschow, M. Alternate substrate inhibition of cholesterol esterase by thieno [2,3-d] [1,3] oxazin-4-ones. J Biol Chem 277, 2002, 24006–13.
  16. [16]. Sravanthi P, Basha SS. Anti-atherosclerotic activity of ethanolic extract of chrysanthemum Indicum l. Flowers against high-fat diet-induced atherosclerosis in male Wistar rats. Asian J Pharm Clin Res 10(9), 2017, 52-6.
  17. [17]. Peng G, Wei YD, Tang J, Peng AY, Rao L, A new synthesis of fully phosphorylated flavones as potent pancreatic cholesterol esterase inhibitors. Org Biomol Chem 9, 2011, 2530-4.
  18. [18]. Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 96, 2002, 67–202.
  19. [19]. Middleton JE, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52, 2000, 673–51.
  20. [20]. Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130, 2000, 2243–50.
  21. [21]. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 342, 1993, 1007–11.
  22. [22]. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ 312, 1996, 478–81.
  23. [23]. Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliovaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 76, 2002, 560–8.
  24. [24]. Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparisonwith placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J 143, 2002, 910–5.
  25. [25]. Kim SH, Kang KW, Kim KW, Kim ND. Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sci 67, 2000, 121–31.
  26. [26]. Kim HP, Son KH, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci 96, 2004, 229– 45.
  27. [27]. Narayana KR, Reddy MS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutical potential. Indian J Pharmacol 33, 2001, 2.
  28. [28]. Mariyappan Palani, Karthi Natesan, Manju Vaiyapuri. Computational studies on different types of apoptotic proteins docked with a dietary flavonoid eriodictyol in colon cancer. Asian J Pharm Clin Res 10(1), 201, 223-6.
  29. [29]. Schames JR, Henchman RH, SeigelJS, Sotriffer CA, Ni H, McCammon A. Discovery of a novel binding trench in HIV integrase. J Med Chem. 47, 2004, 1879- 81.
  30. [30]. Cosconati S, Forli S, Perryman AL, Harris R, Goodsell DS, Olson AJ. Virtual Screening with AutoDock: Theory and practice. Expert Opin Drug Discov 5, 2010, 597- 607.
  31. [31]. Kaur K, Kaur P, Mittal A, Nayak SK, Khatik GL. Design and molecular docking studies of novel antimicrobial peptides using autodock molecular docking software 2017.
  32. DOI:http://dx.doi.org/10.22159/ajpcr.2017.v10s4.21332.
  33. [32]. Goodsell DS, Morris GM, Olson AJ. Automated docking of flexible ligands: Applications of Autodock. J Mol Recog 9, 1996, 1-5.
  34. [33]. Khan F, BAFNA S, Gupta T, Emerson IA.Virtual Screening Of Potential Inhibitors From Herbs For The Treatment Of Breast Cancer. Asian J Pharm Clin Res 10(4), 2017, 62-7.
  35. [34]. Konc J, Konc JT, Penca M, Janezic D. Binding-sites prediction assisting protein-protein docking. Acta Chim Slov 58, 2011, 396–401.
  36. [35]. Umamaheswari M, Madeswaran A, Asokkumar K, Sivashanmugam T, Subhadradevi V, Jagannath P. Study of potential xanthine oxidase inhibitors: In silico and in vitro biological activity. Bangladesh J Pharmacol 6, 2011, 117-23.
  37. [36]. Schoichet BK. Virtual screening of chemical libraries. Nature 43, 2004, 862-5.
  38. [37]. Koppen H. Virtual screening – what does it give us? Curr Opin Drug Disc Dev 12, 2009, 397-407.
  39. [38]. Nerdy. In silico docking roselle (Hibiscus sabdariffa L.) Calyces flavonoids as antimalarial against plasmepsin 1 and plasmepsin 2. Asian J Pharm ClinRes 10(10), 2017, 183-186.
  40. [39]. Azam F, Prasad MVV, Thangavel N. Molecular docking studies of 1-(substituted phenyl) -3- (naphtha [1,2 –d] thiazol -2-yl) urea/thiourea derivatives with human adenosine A2A receptor. Bioinformation 6, 2011, 330-34.
  41. [40]. Sivakumar R, Lokesh N, Rajashekhar A, Ramu N, Saikishore P, Venkatanarayanan R. Docking studies on PPARγ of novel α- phenoxy phenyl propionic acid derivatives as antidiabetic agent. Der Pharmacia Sinica 2, 2011, 327.
  42. [41]. Luskey KL, Stevens B. Human 3-hydroxy-3-methylglutaryl coen¬zyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation. J Biol Chem 260(18), 1985, 10271–7.
  43. [42]. Ulfa DM, Arsianti ADE, Radji M. In Silico Docking Studies of Gallic Acid Structural Analogs as Bcl-Xl Inhibitor in Cancer. Asian J Pharm Clin Res 10(4), 2017, 119-122.
  44. [43]. Collignon B, Schulz R, Smith JC. Task-parallel message passing interface implementation of Autodock4 for docking of very large databases of compounds using high-performance super-computers. J Comput Chem 32, 2011, 1202-09.