Research Article

Docking and Molecular Dynamics Simulations Reveal A Possible Site of Interaction of Olive Leaf Extract Hydroxytyrosol with Polyunsaturated Fatty Acid 5-Lipoxygenase Human Enzyme

Maria Valentini
Center for Advanced Studies, Research and Development in Sardinia (CRS4), Italy
Enrico Pieroni
Center for Advanced Studies, Research and Development in Sardinia (CRS4), Italy
Alessandro Concas
University of Cagliari, Italy
Massimo Pisu
Center for Advanced Studies, Research and Development in Sardinia (CRS4), Italy
* Corresponding author
DOI icon 10.24018/ejbio.2022.3.2.345

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Submitted 2022-02-21
Published 2022-03-23

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Table of Contents

Article Main Content

The polyphenol hydroxytyrosol (HT), a molecule easily extracted from olive oil production waste, has well known antioxidant and anti-inflammatory properties. In literature various bioassays points to a clear inhibitory effects on the polyunsaturated fatty acid 5-lipoxygenase enzyme (LOX5) which is a current target for pharmaceutical intervention for various inflammatory diseases. We have investigated the hypothesis of direct interaction of HT with LOX5 through blind docking and a 200 nanoseconds long molecular dynamics. Analysis of the results highlights the stability of the interaction of HT in the putative binding site with LOX5. This is in accord with the hypothesis of an allosteric way of action of HT to inhibit the activity of the LOX5 also suggesting the use of HT structure as a scaffold to design LOX5 inhibitors with improved activity and specificity.

Keywords: Docking, molecular dynamics, hydroxytyrosol, olive leaf extract, LOX5_HUMAN, 5-lipoxygenase

References

  1. Bertin L, Ferri F, Scoma A, et al. (2011). Recovery of high added value natural polyphenols from actual olive mill wastewater through solid phase extraction. Chem Eng J. 171:1287-1293.
     Google Scholar
  2. Bulotta S, Celano M, Lepore SM, et al. (2014). Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: Focus on protection against cardiovascular and metabolic diseases. J. Transl. Med. 3,12:219.
     Google Scholar
  3. Christman LM, Gu L (2020). Efficacy and mechanisms of dietary polyphenols in mitigating rheumatoid arthritis. J. Funct. Foods. 71:104003.
     Google Scholar
  4. Corrêa TA, Rogero MM (2019). Polyphenols regulating microRNAs and inflammation biomarkers in obesity. Nutrition. 59:150-157.
     Google Scholar
  5. D’Angelo S, Manna C, Migliardi V, et al. (2001). Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil. Drug Metab Dispos. 29(11):1492-1498.
     Google Scholar
  6. De La Puerta R, Gutierrez VR, Hoult JRS (1999). Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol 57:445–449.
     Google Scholar
  7. Frascari D, Bacca AEM, Zama F, et al. (2016). Olive mill wastewater valorisation through phenolic compounds adsorption in a continuous flow column. Chem Eng J. 283:293-303.
     Google Scholar
  8. Gilbert NC, Bartlett SG, Waight MT, et al. (2011). The structure of human 5-lipoxygenase. Science. 331(6014):217–219.
     Google Scholar
  9. Gilbert NC, Gerstmeier J, Schexnaydre EE, et al. (2020). Structural and mechanistic insights into 5-lipoxygenase inhibition by natural products. Nat Chem Biol. 16(7):783-790.
     Google Scholar
  10. Goldsmith CD, Bond DR, Jankowski H, et al. (2018). The olive biophenols oleuropein and hydroxytyrosol selectively reduce proliferation, influence the cell cycle, and induce apoptosis in pancreatic cancer cells. Int J Mol Sci. 19(7):1937.
     Google Scholar
  11. Han J, Talorete TPN, Yamada P, Isoda H (2009). Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology. 59(1):45-53.
     Google Scholar
  12. Hu T, He XW, Jiang JG, Xu XL (2014). Hydroxytyrosol and its potential therapeutic effects. J. Agric. Food Chem. 62(7):1449-1455.
     Google Scholar
  13. Humphrey W, Dalke A, Schulten K (1996). VMD: Visual molecular dynamics. J Mol Graph. 14:33–38.
     Google Scholar
  14. Jemai H, Feki AEL, Sayadi S (2009). Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats. J Agric Food Chem. 14;57(19):8798-8804.
     Google Scholar
  15. Kohyama N, Nagata T, Fujimoto SI, Sekiya K (1997). Inhibition of arachidonate lipoxygenase activities by 2-(3,4-dihydroxyphenyl)ethanol, a phenolic compound from olives. Biosci Biotechnol Biochem 61:347–350.
     Google Scholar
  16. Leri M, Natalello A, Bruzzone E, et al. (2019). Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ 1-42 aggregation. Food Chem Toxicol. 129:1-12.
     Google Scholar
  17. Marković AK, Torić J, Barbarić M, Brala CJ (2019). Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules. 24(10): 2001.
     Google Scholar
  18. Michaud-Agrawal N, Denning EJ, Woolf TB, Beckstein O (2011). MDAnalysis: A toolkit for the analysis of molecular dynamics simulations. J Comput Chem. 32(10):2319-2327.
     Google Scholar
  19. Newcomer ME, Brash AR (2015). The structural basis for specificity in lipoxygenase catalysis. Protein Sci 24:298–309.
     Google Scholar
  20. Nosé S (1984) A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys. 81, 511.
     Google Scholar
  21. Pergola C, Werz O (2010). 5-Lipoxygenase inhibitors: A review of recent developments and patents. Expert Opin. Ther. Pat. 20:355–375.
     Google Scholar
  22. Phillips JC, Braun R, Wang W, et al. (2005). Scalable molecular dynamics with NAMD. J. Comput. Chem. 26:1781–1802.
     Google Scholar
  23. Romani A, Pinelli P, Ieri F, Bernini R (2016). Sustainability, innovation, and green chemistry in the production and valorization of phenolic extracts from Olea europaea L. Sustainability. 8, 1-10.
     Google Scholar
  24. Sadh PK, Duhan S, Duhan JS (2018). Agro-industrial wastes and their utilization using solid state fermentation: a review. Bioresour. Bioprocess. 5:1, 1-15.
     Google Scholar
  25. Schüttelkopf AW, Van Aalten DMF (2004). PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr Sect D Biol Crystallogr. 60(Pt 8):1355-1363.
     Google Scholar
  26. Serra A, Rubió L, Borràs X, et al. (2012). Distribution of olive oil phenolic compounds in rat tissues after administration of a phenolic extract from olive cake. Mol Nutr Food Res. 56(3):486-496.
     Google Scholar
  27. Sterling T, Irwin JJ (2015). ZINC 15 - Ligand Discovery for Everyone. J Chem Inf Model. 55, 11, 2324–2337.
     Google Scholar
  28. Sun L, Luo C, Liu J (2014). Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. 5(8):1909-14.
     Google Scholar
  29. Tomé-Carneiro J, Visioli F (2016). Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine. 23(11):1145-1174.
     Google Scholar
  30. Trott O, Olson AJ (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 31(2): 455–461.
     Google Scholar
  31. Vanommeslaeghe K, Hatcher E, Acharya C, et al. (2010). CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 31:671–690.
     Google Scholar
  32. Vougogiannopoulou K, Lemus C, Halabalaki M, et al. (2014). One-step semisynthesis of oleacein and the determination as a 5-lipoxygenase inhibitor. J Nat Prod. 77:441–445.
     Google Scholar
  33. Zhou Y, Zheng J, Li Y, et al. (2016). Natural polyphenols for prevention and treatment of cancer. Nutrients. 22(8):515.
     Google Scholar
  34. Zubair H, Bhardwaj A, Ahmad A, et al. (2017). Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells. Nutr Cancer. 69(6): 932–942.
     Google Scholar
  35. Zurob E, Cabezas R, Villarroel E, et al. (2020). Design of natural deep eutectic solvents for the ultrasound-assisted extraction of hydroxytyrosol from olive leaves supported by COSMO-RS. Sep Purif Technol. 248:117054.
     Google Scholar