Molecular Biology Reports

, Volume 46, Issue 2, pp 2307–2325 | Cite as

Phytosterols and triterpenes from Morinda lucida Benth. exhibit binding tendency against class I HDAC and HDAC7 isoforms

  • Ahmed Adebayo Ishola
  • Kayode Ezekiel AdewoleEmail author
Original Article


The important role of histone deacetylases (HDACs) in the development of cancer has been demonstrated by various studies. Thus targeting HDACs with inhibitors is a major focus in anticancer drug research. Although few synthetic HDAC inhibitors (HDIs) have been approved for cancer treatment, they have significant undesirable side effects. Therefore emphases have been placed on natural HDIs as substitutes for the synthetic ones. In a bid to identify more HDIs, this study evaluated the binding tendency of compounds derived from Morinda lucida Benth. towards selected HDACs for the discovery of potent HDIs as potential candidates for anticancer therapeutics, based on the report of anticancer potentials of Morinda lucida-derived extracts and compounds. Givinostat and 49 Morinda-lucida derived compounds were docked against selected HDAC isoforms using AutodockVina, while binding interactions were viewed with Discovery Studio Visualizer, BIOVIA, 2016. Druglikeness and Absorption–Distribution–Metabolism–Excretion (ADME) parameters of the top 7 compounds were evaluated using the Swiss online ADME web tool. The results revealed that out of the 49 compounds, 3 phytosterols (campesterol, cycloartenol, and stigmasterol) and 2 triterpenes (oleanolic acid and ursolic acid) exhibited high HDAC inhibitory activity compared to givinostat. These 5 compounds also fulfill oral drugability of Lipinski rule of five. Morinda lucida-derived phytosterols and triterpenes show high binding tendency towards the selected HDACs and exhibited good drugability characteristics and are therefore good candidates for further studies in the search for therapies against abnormalities linked with over-activity of HDACs.


HDACs Morinda lucida Anticancer Phytosterols Triterpenes 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Reddy DS, Wu X, Golub VM et al (2018) Measuring histone deacetylase inhibition in the brain. Curr Protoc Pharmacol 1–14.
  2. 2.
    Singh AK, Bishayee A, Pandey AK (2018) Targeting histone deacetylases with natural and synthetic agents: an emerging strategy. Nutrients 10:1–31. Google Scholar
  3. 3.
    Kumar S, Ahmad M, Waseem M, Pandey AK (2015) Drug targets for cancer treatment: an overview. Med Chem (Los Angeles) 5:115–123CrossRefGoogle Scholar
  4. 4.
    Sharma U, Sharma A, Pandey AK (2016) Medicinal attributes of major phenylpropanoids present in cinnamon. BMC Complement Altern Med 16:156CrossRefGoogle Scholar
  5. 5.
    Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:1–25. CrossRefGoogle Scholar
  6. 6.
    Ganai SA, Farooq Z, Banday S, Altaf M (2018) In silico approaches for investigating the binding propensity of apigenin and luteolin against class i HDAC isoforms. Future Med Chem. Google Scholar
  7. 7.
    Seto E, Yoshida M (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol 6:a018713CrossRefGoogle Scholar
  8. 8.
    Barneda-Zahonero B, Parra M (2012) Histone deacetylases and cancer. Mol Oncol 6:579–589. CrossRefGoogle Scholar
  9. 9.
    De Ruijter A, Van Gennip A, Caron H et al (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749CrossRefGoogle Scholar
  10. 10.
    Ganai S (2016) Novel approaches towards designing of isoform-selective inhibitors against class ii histone deacetylases: the acute requirement for targetted anticancer therapy. CurrTopMedChem 16:2441–2452Google Scholar
  11. 11.
    Mottamal M, Zheng S, Huang T, Wang G (2015) Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20:3898–3941CrossRefGoogle Scholar
  12. 12.
    Ropero S, Esteller M (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1:19–25. CrossRefGoogle Scholar
  13. 13.
    Wilson A, Byun D, Popova N (2006) Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem 281:13548–13558CrossRefGoogle Scholar
  14. 14.
    Lagger S, Meunier DMM et al (2010) Crucial function ofhistone deacetylase 1 for differentiation of teratomas in mice and humans. EMBO J 29:3992–4007CrossRefGoogle Scholar
  15. 15.
    Halkidou K, Gaughan L, Cook S et al (2004) Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59:177–189CrossRefGoogle Scholar
  16. 16.
    Song J, Noh J, Lee J (2005) Increased expression ofhistone deacetylase 2 is found in human gastric cancer. APMIS 113:264–268CrossRefGoogle Scholar
  17. 17.
    Huang B, Laban M, Leung C (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent ofhistone deacetylase 1. Cell Death Differ 12:395–404CrossRefGoogle Scholar
  18. 18.
    Muller BM, Jana LKA et al (2013) Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer-overexpression ofHDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer 13:215CrossRefGoogle Scholar
  19. 19.
    Spurling C, Godman C, Noonan E et al (2008) HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol Carcinog 47:137–147CrossRefGoogle Scholar
  20. 20.
    Oehme I, Deubzer H, Wegener D (2009) Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 5:91–99CrossRefGoogle Scholar
  21. 21.
    Park S, Jun J, Jeong K (2011) Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep 25:677–1681Google Scholar
  22. 22.
    Ahn M-Y, Yoon J-H (2017) Histone deacetylase 7 silencing induces apoptosis and autophagy in salivary mucoepidermoid carcinoma cells. J Oral Pathol Med 46:276–283. CrossRefGoogle Scholar
  23. 23.
    Pandey M, Kaur P, Shukla S et al (2012) Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol Carcinog 51:952–962CrossRefGoogle Scholar
  24. 24.
    Attoub S, Hassan A, Vanhoecke B (2011) Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur J Pharmacol 651:18–25CrossRefGoogle Scholar
  25. 25.
    Soflaei SS, Momtazi-Borojeni AA, Majeed M et al (2018) Curcumin: a natural Pan-HDAC inhibitor in cancer. Curr Pharm Des 24:123–129. CrossRefGoogle Scholar
  26. 26.
    Murugan K, Sangeetha S, Ranjitha S et al (2015) HDACiDB: a database for histone deacetylase inhibitors. Drug Des Devel Ther 9:2257–2264CrossRefGoogle Scholar
  27. 27.
    Sowemimo AA, Fakoya FA, Awopetu I et al (2007) Toxicity and mutagenic activity of some selected Nigerian plants. J Ethnopharmacol 113:427–432. CrossRefGoogle Scholar
  28. 28.
    Ashidi JS, Houghton PJ, Hylands PJ, Efferth T (2010) Ethnobotanical survey and cytotoxicity testing of plants of South-western Nigeria used to treat cancer, with isolation of cytotoxic constituents from Cajanus cajan Millsp. leaves. J Ethnopharmacol 128:501–512. CrossRefGoogle Scholar
  29. 29.
    Durodola JI (1974) Anti-neoplastic property of crystalline compound extracted from Morinda lucida. Planta Med 26:208–211CrossRefGoogle Scholar
  30. 30.
    Appiah-opong R, Tuffour I, Annor GK et al (2016) Antiproliferative, antioxidant activities and apoptosis induction by Morinda lucida and Taraxacum officinale in human HL-60 leukemia cells. J Glob Biosci 5:4281–4291Google Scholar
  31. 31.
    Nweze NE (2012) In vitro anti-trypanosomal activity of Morinda lucida leaves. African J Biotechnol 11:1812–1817. Google Scholar
  32. 32.
    Samje M, Metuge J, Mbah J et al (2014) In vitro anti- Onchocerca ochengi activities of extracts and chromatographic fractions of Craterispermum laurinum and Morinda lucida. BMC Complement Altern Med 14:1–12. CrossRefGoogle Scholar
  33. 33.
    Suzuki M, Tung HN, Kwofie KD et al (2015) New anti-trypanosomal active tetracyclic iridoid isolated from Morinda lucida Benth. Biorgan Med Chem Lett http://dx:1–4.
  34. 34.
    O’Boyle NM, Banck M, James CA et al (2011) Open babel: an open chemical toolbox. J Cheminform 3:33. CrossRefGoogle Scholar
  35. 35.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461Google Scholar
  36. 36.
    McGinnity DF, Collington J, Austin RP, Riley RJ (2007) Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. Curr Drug Metab. Google Scholar
  37. 37.
    Paul Gleeson M, Hersey A, Hannongbua S (2011) In-silico ADME models: a general assessment of their utility in drug discovery applications. Curr Top Med Chem. Google Scholar
  38. 38.
    Daina A, Michielin O, Zoete V (2014) ILOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model 54:3284–3301. CrossRefGoogle Scholar
  39. 39.
    Daina A, Zoete V (2016) A BOILED-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 11:1117–1121CrossRefGoogle Scholar
  40. 40.
    Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. CrossRefGoogle Scholar
  41. 41.
    Huang SY, Zou X (2010) Advances and challenges in protein-ligand docking. Int J Mol Sci 11(8):3016–3034CrossRefGoogle Scholar
  42. 42.
    Raj RA, John Milton MC, Prakasam A et al (2018) In silico molecular docking of bioactive compound Pregnan-20-one,5,6-epoxy-3,17,dihydroxy-16 methyl-[3a,5a,6a,16a] with brain cancer protein(1qh4): a promising molecular target. 9:51–55Google Scholar
  43. 43.
    Hsu KC, Liu CY, Lin TE et al (2017) Novel class IIA-selective histone deacetylase inhibitors discovered using an in silico virtual screening approach. Sci Rep 7(1):3228. CrossRefGoogle Scholar
  44. 44.
    Yoon S, Eom GH (2016) HDAC and HDAC inhibitor: from cancer to cardiovascular diseases. Chonnam Med J 52(1):1 CrossRefGoogle Scholar
  45. 45.
    Tambunan USF, Bramantya N, Parikesit AA (2011) In silico modification of suberoylanilide hydroxamic acid (SAHA) as potential inhibitor for class II histone deacetylase (HDAC). BMC Bioinform. Google Scholar
  46. 46.
    Awad AB, Fink CS (2000) Phytosterols as anticancer dietary components: evidence and mechanism of action. J Nutr 130:2127–2130CrossRefGoogle Scholar
  47. 47.
    Zhang Z, Luo Z, Shi H et al (2017) Research advance of functional plant pharmaceutical cycloartenol about pharmacological and physiological activity. J Chinese Mater medica 42:433–437Google Scholar
  48. 48.
    da Silva I, Kaluderovic G, de Oliveira P et al (2018) Apoptosis caused by triterpenes and phytosterols and antioxidant activity of an enriched flavonoid extract from Passiflora mucronata. Anticancer Agents Med Chem. Google Scholar
  49. 49.
    Choi J, Lee E, Lee H et al (2007) Identification of campesterol from Chrysanthemum coronarium L. and its antiangiogenic activities. Phyther Res 21:954–959. CrossRefGoogle Scholar
  50. 50.
    Kangsamaksin T, Chaithongyot S, Wootthichairangsan C (2017) Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor- α. PLoS One 12:1–16. CrossRefGoogle Scholar
  51. 51.
    Petronelli A, Pannitteri G, Testa U (2009) Triterpenoids as new promising anticancer drugs. Anticancer Drugs 20:880–892. CrossRefGoogle Scholar
  52. 52.
    Chen I, Lu M, Du Y et al (2009) Cytotoxic triterpenoids from the stems of Microtropis japonica. J Nat Prod 72:6–11Google Scholar
  53. 53.
    Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44:235–249CrossRefGoogle Scholar
  54. 54.
    Liu J (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 49:57–68CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of Life SciencesUniversity of IlorinIlorinNigeria
  2. 2.Biochemistry Unit, Department of Chemical Sciences, Faculty of Natural SciencesAjayi Crowther University OyoOyoNigeria

Personalised recommendations