Advertisement

Identification of Lead Molecules in Garcinia mangostana L. Against Pancreatic Cholesterol Esterase Activity: An In Silico Approach

  • George Kadakasseril Varghese
  • Rini Abraham
  • Nisha N. Chandran
  • Solomon Habtemariam
Original Research Article

Abstract

Hypercholesterolemia is one of the major risk factors for the development and progression of atherosclerosis. Hence, inhibitors of cholesterol absorption have been investigated for decades as a strategy to prevent and treat cardiovascular diseases associated with hypercholesterolemia. Cholesterol esterase (CEase) in pancreatic juice plays a vital role in the hydrolysis of dietary cholesterol esters to cholesterol and fatty acids. Since inhibition of CEase might lead to a reduction of cholesterol absorption, an attempt is made in this study to identify lead molecules of Garcinia mangostana by the in silico approach. The study employed software applications viz., AutoDock 4.2 and GOLD Suite of Programs 5.2. The study revealed the efficacy of three compounds viz., epicatechin, euxanthone, and 1,3,5,6-tetrahydroxy-xanthone, which exhibited least binding energy in AutoDock and moderate scoring in GOLD. The molecular properties as well as biological activity of these three compounds were predicted by molinspiration prediction tool. The results show the crucial role of polyphenolic compounds to limit the activity of CEase. The drug-likeness prediction revealed the prospects of the identified lead molecules as potential drug candidates.

Keywords

Garcinia mangostana Cholesterol esterase AutoDock GOLD Epicatechin Euxanthone Tetrahydroxy-xanthone 

Notes

Acknowledgements

The corresponding author acknowledges KSCSTE for Emeritus fellowship and financial assistance. We also acknowledge Rev. Dr. Tomy Joseph Padinjareveettil (Principal, SB College, Changanassery), Dr. P.G. Latha, and Dr. P. N. Krishnan (Jawaharlal Nehru Tropical Botanic Garden & Research Institute, Thiruvananthapuram) for their comprehensive help and support.

References

  1. 1.
    Gordon T, Kannel WB, Castelli WP, Dawber TR (1981) Lipoproteins, cardiovascular disease, and death: the Framingham study. Arch Intern Med 141(9):1128–1131CrossRefPubMedGoogle Scholar
  2. 2.
    Otunola GA, Oloyede OB, Oladiji AT, Afolayan AA (2010) Effects of diet-induced hypercholesterolemia on the lipid profile and some enzyme activities in female wistar rats. Afr J Biochem Res 4(6):149–154Google Scholar
  3. 3.
    Craig CR, Stitzel RE (2004) Modern pharmacology with clinical applications, 6th edn. Lippincott Williams & Wilkins, London, pp 268–277Google Scholar
  4. 4.
    Singh BB, Vinjamury PS, Der-Martirosian C, Kubik E, Mishra CL, Shepard PN, Singh JV, Meier M, Madhu GS (2007) Ayurvedic and collateral herbal treatments for hyperlipidemia: a systematic review of randomized controlled trials and quasi-experimental designs. Altern Ther Health Med 13(4):22–28PubMedGoogle Scholar
  5. 5.
    Hongbao Ma (2004) Cholesterol and human health. Nat Sci 2(4):17–21Google Scholar
  6. 6.
    Stancu C, Anca S (2001) Statins: mechanism of action and effects. J Cell Mol Med 5(4):378–387CrossRefPubMedGoogle Scholar
  7. 7.
    Asashina M, Sato M, Imaizumi K (2005) Genetic analysis of diet induced hypercholesterolemia in exogenously hypercholesterolemic (ExHC) rats. J Lipid Res 46:2289–2294CrossRefGoogle Scholar
  8. 8.
    Charles BE (2005) Hyperlipidemia. Prim Care Clin Off Pract 32:1027–1055CrossRefGoogle Scholar
  9. 9.
    Wang CS, Hartsuck JA (1993) Biochim Biophys Acta 1166:1–19CrossRefPubMedGoogle Scholar
  10. 10.
    Heynekamp JJ, Hunsaker LA, Vander JTA, Royer RE, Deck LM, Vander JDL (2008) Isocoumarin-based inhibitors of pancreatic cholesterol esterase. Bio-org Med Chem 16(9):5285–5294CrossRefGoogle Scholar
  11. 11.
    Pietsch M, Gutschow M (2002) Alternate substrate inhibition of cholesterol esterase by thieno[2,3-d][1,3]oxazin-4-ones. J Biol Chem 277(27):24006–24013CrossRefPubMedGoogle Scholar
  12. 12.
    Howels PN, Carter CP, Hui DY (1996) Dietary free and esterified cholesterol absorption in cholesterol esterase (bile salt-stimulated lipase) gene-targeted mice. J Biol Chem 271(12):7196–7202CrossRefGoogle Scholar
  13. 13.
    John S, Thangapandian S, Sakkiah S, Lee KW (2011) Discovery of potential pancreatic cholesterol esterase inhibitors using pharmacophore modelling, virtual screening, and optimization studies. J Enzyme Inhib Med Chem 26(4):535–545CrossRefPubMedGoogle Scholar
  14. 14.
    Li F, Hui DY (1998) Synthesis and secretion of the pancreatic-type carboxyl ester lipase by human endothelial cells. Biochem J 329:675–679CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chen JCH, Miercke LJW, Krucinski J, Starr JR, Saenz G, Wang X, Spilburg CA, Lange LG, Ellsworth JLO, Stroud RM (1998) Structure of bovine pancreatic cholesterol esterase at 1.6 Å: novel structural features involved in lipase activation. Biochemistry 37(15):5107–5117CrossRefPubMedGoogle Scholar
  16. 16.
    Hui DY (1996) Molecular biology of enzymes involved with cholesterol ester hydrolysis in mammalian tissues. Biochim Biophys Acta 1303(1):1–14CrossRefPubMedGoogle Scholar
  17. 17.
    Lopez-Candales A, Bosner MS, Spilburg CA, Lange LG (1993) Cholesterol transport function of pancreatic cholesterol esterase: directed sterol uptake and esterification in enterocytes. Biochemistry 32:12085–12089CrossRefPubMedGoogle Scholar
  18. 18.
    Myers Payne SC, Hui DY, Brockman HL, Schroeder F (1995) Cholesterol esterase: cholesterol transfer protein. Biochemistry 34(12):3942–3947CrossRefPubMedGoogle Scholar
  19. 19.
    Ikeda I, Matsuoka R, Hamada T, Mitsui K, Imabayashi S, Uchino A, Sato M, Kuwano E, Itamura T, Yamada K, Tanaka K, Imaizumi K (2002) Cholesterol esterase accelerates intestinal cholesterol absorption. Biochim Biophys Acta 1571(1):34–44CrossRefPubMedGoogle Scholar
  20. 20.
    Shyh-Ying Chiou, Gin-Win Lai, Long-Yau Lin, Gialih Lin (2005) Kinetics and mechanisms of cholesterol esterase inhibition by cardiovascular drugs in vitro. Indian J Biochem Biophys 43:52–55Google Scholar
  21. 21.
    Kim SD (2010) Isolation, structure and cholesterol esterase inhibitory activity of a polysaccharide, PS-A, from Cordyceps sinensis. J Korean Soc Appl Biol Chem 53(6):784–789CrossRefGoogle Scholar
  22. 22.
    Kumar P, Sivashanmugam T, Umamaheswari M, Subhadradevi V, Jagannath P (2011) Cholesterol esterase enzyme inhibitory and antioxidant activities of leaves of Camellia sinensis (L) Kuntze. using in vitro models. Int J Pharm Sci Res 2(10):2675–2680Google Scholar
  23. 23.
    Krause BR, Sliskovic DR, Anderson M, Homan R (1998) Lipid-lowering effects of WAY-121,898, an inhibitor of pancreatic cholesteryl ester hydrolase. Lipids 33(5):489–498CrossRefPubMedGoogle Scholar
  24. 24.
    Saraswathi NT, Gnanam FD (1997) Effect of medicinal plants on the crystallization of cholesterol. J Cryst Growth 179(3–4):611–617CrossRefGoogle Scholar
  25. 25.
    Ghalehkandi JG, Asghari A, Nobar RSD, Yeghaneh A (2012) Hypolipidemic effects of aqueous extract of onion (Allium cepa. Linn) on serum levels of cholesterol, triglycerides, LDL and HDL compared with Zn sulfate supplementation in the rats. Eur J Exp Biol 2(5):1745–1749Google Scholar
  26. 26.
    Krishnakumari S, Priya K (2006) Hypolipidemic efficacy of Achyranthes aspera on lipid profile in sesame oil fed rats. Anc Sci Life 25(3–4):49–56PubMedPubMedCentralGoogle Scholar
  27. 27.
    Ammal SM, George KV, Jayakumari I (2007) Effect of phytoactive compounds on in vitro cholesterol crystal growth. Cryst Res Technol 42(9):876–880CrossRefGoogle Scholar
  28. 28.
    Beg M, Singhal KC, Afzaal S (1996) A study of effect of guggulsterone on hyperlipidemia of secondary glomerulopathy. Indian J Physiol Pharmacol l40(3):237–240Google Scholar
  29. 29.
    Abraham R, Varghese GK, Nisha NC, Sreekumar S (2014) Molecular docking of Terminalia cuneata on cholesteryl esterase. Int J Comput Bioinf In Silico Model 3(1):327–331Google Scholar
  30. 30.
    Asmaa BH, Ream N (2016) In vitro screening of the pancreatic cholesterol esterase inhibitory activity of some medicinal plants grown in Syria. Int J Pharmacogn Phytochem Res 8(8):1432–1436Google Scholar
  31. 31.
    Balasubramanian K, Rajagopalan K (1988) Novel xanthones from Garcinia mangostana: structures of BR-xanthone-A and BR-xanthone-B. Phytochemistry 27:1552–1554CrossRefGoogle Scholar
  32. 32.
    Mahabusarakam W, Wiriyachitra P, Phongpaichit S (1986) Antimicrobial activities of chemical constituents from G. mangostana Linn. J Sci Soc Thailand 12:239–240CrossRefGoogle Scholar
  33. 33.
    Mahabusarakam W, Wiriyachtra P, Taylor W (1987) Chemical constituents of Garcinia mangostana. J Nat Prod 50:474–478CrossRefGoogle Scholar
  34. 34.
    Weecharangsan W, Opanasopit P, Sukma M, Ngawhirunpat T, Sotanaphun U, Siripong P (2006) Antioxidative and neuroprotective activities of extracts from the fruit hull of mangosteen (Garcinia mangostana Linn.). Med Princ Pract 15:281–287CrossRefPubMedGoogle Scholar
  35. 35.
    Nakatani K, Nakahata N, Arakawa T, Yasuda H, Ohizumi Y (2002) Inhibition of cyclo-oxygenase and prostaglandin E2 synthesis by -mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. Biochem Pharmacol 63(1):73–79CrossRefPubMedGoogle Scholar
  36. 36.
    Akao Y, Nakagawa Y, Iinuma M, Nozawa Y (2008) Anti-cancer effects of xanthones from pericarps of mangosteen. Int J Mol Sci 9:355–370CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ryu HW, Cho JK, Curtis-Long MJ, Yuk HJ, Kim YS, Jung S, Kim YS, Lee BW, Park KH (2011) α-Glucosidase inhibition and anti hyperglycemic activity of prenylated xanthones from Garcinia mangostana. Phytochemistry 72:2148–2154CrossRefPubMedGoogle Scholar
  38. 38.
    Nelli GB, Kilari EK (2013) Antidiabetic effect of α-mangostin and its protective role in sexual dysfunction of streptozotocin induced diabetic male rats. Syst Biol Reprod Med 59:319–328CrossRefPubMedGoogle Scholar
  39. 39.
    Adiputro D, Widodo MA, Rochmad R, Sargowo D (2013) Extract of mangosteen increases high density lipoprotein levels in rats fed high lipid. Univ Med 32(3):37–43Google Scholar
  40. 40.
    Sundaram BM, Gopalakrishnan C, Subramanian S, Shankaranarayanan D, Kameswaran L (1983) Antimicrobial activities of Garcinia mangostana. Planta Med 48:59–60CrossRefPubMedGoogle Scholar
  41. 41.
    Vishnupriya V, Mallika J, Surapaneni KM, Saraswathi P, Chandra SGVS (2010) Antimicrobial activity of pericarp extract of Garcinia mangostana Linn. Int J Pharma Sci Res 1(8):278–281Google Scholar
  42. 42.
    Williams P, Ongsakul M, Proudfoot J, Croft K, Beilin L (1995) Mangostin inhibits the oxidative modification of human low density lipoprotein. Free Radic Res 23(2):175–184CrossRefPubMedGoogle Scholar
  43. 43.
    Hanna L, Maria L, Jerzy D, Ratiporn H, Sumitra P, Yong-Seo P, Soon-Teck J, Seong-Gook K, Simon T, Shela G (2006) Bioactive properties of Snake fruit (Salacca edulis Reinw) and Mangosteen (Garcinia mangostana) and their influence on plasma lipid profile and antioxidant activity in rats fed cholesterol. Eur Food Res Technol 223:697–703CrossRefGoogle Scholar
  44. 44.
    Obolskiy D, Pischel I, Siriwatanametanon N, Heinrich M (2009) Garcinia mangostana L.: a phytochemical and pharmacological review. Phytother Res 23(8):1047–1196CrossRefPubMedGoogle Scholar
  45. 45.
    Aung SD, Aye AT, San SA, Maung MH (2005) Study on the natural pigments present in the Hulls of Garcinia mangostana Linn. J Myanmar Acad Arts Sci 3(1):173–183Google Scholar
  46. 46.
    Rice-Evans CA, Miller NJ, Paganga G (1997) Antioxidant properties of phenolic compounds. Trends Plant Sci 2:152–159CrossRefGoogle Scholar
  47. 47.
    Rice-Evans CA, Miller NJ, Papanga G (1996) Antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956CrossRefPubMedGoogle Scholar
  48. 48.
    Haruenkit R, Poovarodom S, Leontowicz H, Leontowicz M, Sajewicz M, Kowalska T, Delgado-Licon E, Rocha-Guzmán NE, Gallegos-Infante JA, Trakhtenberg S, Gorinstein S (2007) Comparative study of health properties and nutritional value of durian, mangosteen and snake fruit: experiments in vitro and in vivo. J Agric Food Chem 55(14):5842–5849CrossRefPubMedGoogle Scholar
  49. 49.
    Taher M, Tg ZTM, Susanti D, Zakaria ZA (2016) Hypoglycaemic activity of ethanolic extract of Garcinia mangostana Linn. in normoglycaemic and streptozotocin-induced diabetic rats. BMC Complement Altern Med 21(16):135. doi: 10.1186/s12906-016-1118-9 CrossRefGoogle Scholar
  50. 50.
    Chae HS, Kim YM, Bae JK, Sorchhann S, Yim S, Han L, Paik JH, Choi YH, Chin YW (2016) Mangosteen extract attenuates the metabolic disorders of high-fat-fed mice by activating AMPK. J Med Food 19(2):148–154. doi: 10.1089/jmt.2015.3496 Equb 2015 Oct 9 CrossRefPubMedGoogle Scholar
  51. 51.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Nematollahi A, Aminimoghadamfarouj N, Jalilvand MR, VakiliSeyed A (2012) Molecular docking studies of luteolin derivatives, from Biebersteinia multifida DC., as novel HMG-CoA reductase inhibitors. Int J Chem Tech Res 2:733–738Google Scholar
  53. 53.
    Jhansi RG, Vinoth M, Anitha P (2011) Molecular docking studies on oxidosqualene cyclase with 4-piperidino pyridine and 4-piperidino pyrimidine as its inhibitors. J Bioinf Seq Anal 3(3):31–36Google Scholar
  54. 54.
    Verma A (2012) Lead finding from Phyllanthus debelis with hepatoprotective potentials. Asian Pac J Trop Biomed 2(3):1735–1737CrossRefGoogle Scholar
  55. 55.
    Lalitha P, Sivakamasundari S (2010) Calculation of molecular lipophilicity and drug likeness for few heterocycles. Orient J Chem 26:135–141Google Scholar
  56. 56.
    Mohan H (2010) Textbook of Pathology, 6th edn. Jaypee Brothers Medical Publishers, New DelhiCrossRefGoogle Scholar
  57. 57.
    Ngamukote S, Makynen K, Thilawech T, Adisakwattana S (2011) Cholesterol lowering activity of the major polyphenols in grape seed. Molecules 16(6):5054–5061CrossRefPubMedGoogle Scholar
  58. 58.
    Sivashanmugam T, Muthukrishnan S, Umamaheswari M, Asokkumar K, Subhadradevi V, Jagannath P, Madeswaran A (2013) Discovery of potential cholesterol esterase inhibitors using in silico docking studies. Bangladesh J Pharmacol 8:223–229CrossRefGoogle Scholar
  59. 59.
    Habtemariam S, Varghese GK (2014) The antidiabetic therapeutic potential of dietary polyphenols. Curr Pharm Biotechnol 15(4):391–400CrossRefPubMedGoogle Scholar
  60. 60.
    Ganugapati J, Mukkavalli S, Sahithi A (2011) Docking studies of green tea flavonoids as insulin mimetics. Int J Comput Appl 30(4):48–52Google Scholar
  61. 61.
    Cyranski MK (2005) Energetic aspects of cyclic Pi-electron delocalization: evaluation of the methods of estimating aromatic stabilization energies. Chem Rev 105(10):3773–3811CrossRefPubMedGoogle Scholar
  62. 62.
    Krygowski TM, Cyranski MK (2009) Topics in heterocyclic chemistry. Springer, Berlin HeidelbergGoogle Scholar
  63. 63.
    Balaban AT, Schleyer PVR, Rzepa HS (2005) Crocker, not Armit and Robinson, begat the six aromatic electrons. Chem Rev 105:3436CrossRefPubMedGoogle Scholar
  64. 64.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26CrossRefPubMedGoogle Scholar
  65. 65.
    Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2(4):541–553CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • George Kadakasseril Varghese
    • 1
  • Rini Abraham
    • 2
  • Nisha N. Chandran
    • 3
  • Solomon Habtemariam
    • 4
  1. 1.Department of BotanySt. Berchmans’ CollegeChanganasseryIndia
  2. 2.School of Environmental SciencesMahatma Gandhi UniversityKottayamIndia
  3. 3.Biotechnology and Bioinformatics Division, Saraswathy Thangavelu CentreJawaharlal Nehru Tropical Botanic Garden & Research InstituteThiruvananthapuramIndia
  4. 4.Pharmacognosy Research Laboratories, Medway School of ScienceUniversity of Greenwich, KENTMedwayUK

Personalised recommendations