In-silico ADMET profile of Ellagic Acid from Syzygium cumini: A Natural Biaryl Polyphenol with Therapeutic Potential to Overcome Diabetic Associated Vascular Complications

  • S. Ramya The Thavaram Trust, Thiruppalai - 625014, Madurai, TamilNadu, India
  • M. Murugan PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India
  • K. Krishnaveni Department of Zoology, GTN College, Dindigul, TamilNadu, India
  • M. Sabitha PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India
  • C. Kandeepan PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India
  • R. Jayakumararaj Department of Botany, Government Arts College, Melur – 625106, Madurai, TamilNadu, India

Abstract

Plant Based Natural Products (PBNPs) are the primary source of natural antioxidants capable of neutralizing or eliminating harmful Reactive Oxygen Species (ROS). Oxidative stress contributes not only to the pathogenesis of type 2 diabetes (T2DM) but also to diabetic related vascular complications by lipid peroxidation. Oxidation induced DNA and protein damage leads to development of vascular complications like coronary heart disease, CVD, stroke, neuropathy, retinopathy, nephropathy, CKD, and other long term complications associated with diabetics. Likewise Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. Ellagic acid (EA) is a bioactive secondary metabolite widely distributed in vegetables and fruits (Strawberry, Grapes, Blackberry, Raspberry, Plums etc.) Chemically, EA is 2,3,7,8-tetrahydroxychromeno [5,4, -cde] chromene-5, 10-dione, a heterotetracyclic dimer of Gallic Acid (GA) molecules formed by oxidative aromatic coupling involving intramolecular lactonization. EA is associated with pharmacological activities such as anti-inflammatory, neuroprotective, cardio-protective, antioxidant, anti-mutagenic, multidrug resistance etc. EA has been marketed as a dietary supplement with claimed benefits against cancer, CVD, CKD and other metabolic disorders. However, pharmacological limitation of EA is attributed to its low solubility in water and reduced bioavailability. In the present study, bimolecular potential of EA has been bioprospected in the revised framework of ADMET pharmacoinformatics to further widen its biomedical applications.


Keywords: ADMET; Pharmacoinformatics; Ellagic Acid; Gallic Acid; Syzygium cumini; Alagarkovil Reserve Forest (ARF); Reactive Oxygen Species (ROS)

Keywords: ADMET, Pharmacoinformatics, Ellagic Acid, Gallic Acid, Syzygium cumini, Alagarkovil Reserve Forest (ARF), Reactive Oxygen Species (ROS)

Downloads

Download data is not yet available.

Author Biographies

S. Ramya, The Thavaram Trust, Thiruppalai - 625014, Madurai, TamilNadu, India

The Thavaram Trust, Thiruppalai - 625014, Madurai, TamilNadu, India

M. Murugan, PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

K. Krishnaveni, Department of Zoology, GTN College, Dindigul, TamilNadu, India

Department of Zoology, GTN College, Dindigul, TamilNadu, India

M. Sabitha, PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

C. Kandeepan, PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

PG Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani-624601, India

R. Jayakumararaj, Department of Botany, Government Arts College, Melur – 625106, Madurai, TamilNadu, India

Department of Botany, Government Arts College, Melur – 625106, Madurai, TamilNadu, India

References

1. Agrawal OD, Kulkarni YA. Mini-Review of Analytical Methods used in Quantification of Ellagic Acid. Reviews in Analytical Chemistry. 2020; 39(1):31-44. https://doi.org/10.1515/revac-2020-0113
2. Gajera HP, Gevariya SN, Hirpara DG, Patel SV, Golakiya BA. Antidiabetic and antioxidant functionality associated with phenolic constituents from fruit parts of indigenous black jamun (Syzygium cumini L.) landraces. J Food Sci Technol 2017; 54:3180-3191 https://doi.org/10.1007/s13197-017-2756-8
3. Meyer AS, Heinonen M, Frankel EN. Antioxidant Interactions of Catechin, Cyanidin, Caffeic acid, Quercetin, and Ellagic acid on Human LDL Oxidation. Food Chem. 1998; 61(1-2):71-5. https://doi.org/10.1016/S0308-8146(97)00100-3
4. Priyadarsini KI, Khopde SM, Kumar SS, Mohan H. Free Radical Studies of Ellagic acid, a Natural Phenolic Antioxidant. J Agric Food Chem. 2002; 50(7):2200-6. https://doi.org/10.1021/jf011275g
5. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, et al. In Vitro Antiproliferative, Apoptotic and Antioxidant Activities of Punicalagin, Ellagic acid and a Total Pomegranate Tannin Extract Are Enhanced in Combination with Other Polyphenols as Found in Pomegranate Juice. J Nutr Biochem. 2005; 16(6):360-7. https://doi.org/10.1016/j.jnutbio.2005.01.006
6. Hussein MZ, Al Ali SH, Zainal Z, Hakim MN. Development of Antiproliferative Nanohybrid Compound with Controlled Release Property Using Ellagic acid as the Active Agent. Int J Nanomedicine. 2011; 6(1):1373-83. https://doi.org/10.2147/IJN.S21567
7. Soh PN, Witkowski B, Olagnier D, Nicolau ML, Garcia-Alvarez MC, Berry A, et al. In Vitro and In Vivo Properties of Ellagic acid in Malaria Treatment. Antimicrob Agents Chemother. 2009; 53(3):1100-6. https://doi.org/10.1128/AAC.01175-08
8. Corbett S, Daniel J, Drayton R, Field M, Steinhardt R, Garrett N. Evaluation of the Anti-Inflammatory Effects of Ellagic acid. J Perianesth Nurs. 2010; 25(4):214-20. https://doi.org/10.1016/j.jopan.2010.05.011
9. García-Niño WR, Zazueta C. Ellagic acid: Pharmacological Activities and Molecular Mechanisms Involved in Liver Protection. Pharmacol Res. 2015; 97:84-103. https://doi.org/10.1016/j.phrs.2015.04.008
10. Ahn D, Putt D, Kresty L, Stoner GD, Fromm D, Hollenberg PF. The Effects of Dietary Ellagic acid on Rat Hepatic and Esophageal Mucosal Cytochromes P450 and Phase II Enzymes. Carcinogenesis. 1996; 17(4):821-8. https://doi.org/10.1093/carcin/17.4.821
11. Umesalma S, Sudhandiran G. Differential Inhibitory Effects of the Polyphenol Ellagic acid on Inflammatory Mediators NF-KB, INOS, COX-2, TNF-α, and IL-6 in 1,2-Dimethylhydrazine-Induced Rat Colon Carcinogenesis. Basic Clin Pharmacol Toxicol. 2010; 107(2):650-5. https://doi.org/10.1111/j.1742-7843.2010.00565.x
12. Chen GH, Lin YL, Hsu WL, Hsieh SK, Tzen JT. Significant Elevation of Antiviral Activity of Strictinin from Pu'er Tea after Thermal Degradation to Ellagic acid and Gallic acid. Yao Wu Shi Pin Fen Xi. 2015; 23(1):116-23. https://doi.org/10.1016/j.jfda.2014.07.007
13. Park SW, Kwon MJ, Yoo JY, Choi HJ, Ahn YJ. Antiviral activity and possible mode of action of ellagic acid identified in Lagerstroemia speciosa Leaves toward Human Rhinoviruses. BMC Complement Altern Med. 2014; 14(1):171. https://doi.org/10.1186/1472-6882-14-171
14. Evtyugin DD, Magina S, Evtuguin DV. Recent advances in the production and applications of ellagic acid and its derivatives. A review. Molecules. 2020 Jan; 25(12):2745. https://doi.org/10.3390/molecules25122745
15. Alfei S, Turrini F, Catena S, Zunin P, Grilli M, Pittaluga AM, Boggia R. Ellagic acid a multi-target bioactive compound for drug discovery in CNS? A narrative review. European journal of medicinal chemistry. 2019 Dec 1; 183:111724. https://doi.org/10.1016/j.ejmech.2019.111724
16. Kumar Singh A, Cabral C, Kumar R, Ganguly R, Kumar Rana H, Gupta A, Rosaria Lauro M, Carbone C, Reis F, Pandey AK. Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients. 2019 Sep; 11(9):2216. https://doi.org/10.3390/nu11092216
17. Zhang, H.; Xu, H.; Ashby, C.R., Jr.; Assaraf, Y.G.; Chen, Z.S.; Liu, H.M. Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp). Med. Res. Rev. 2021, 41, 525-555. https://doi.org/10.1002/med.21739
18. Yoganathan S, Alagaratnam A, Acharekar N, Kong J. Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer. Cells. 2021 Feb; 10(2):458. https://doi.org/10.3390/cells10020458
19. Gupta A, Singh AK, Kumar R, Jamieson S, Pandey AK, Bishayee A. Neuroprotective Potential of Ellagic Acid: A Critical Review. Advances in Nutrition. 2021:1-28; doi: https://doi.org/10.1093/advances/nmab007
20. Ríos JL, Giner RM, Marín M, Recio MC. A pharmacological update of ellagic acid. Planta medica. 2018 Oct; 84(15):1068-93. https://doi.org/10.1055/a-0633-9492
21. Ruan ZP, Zhang LL, Lin YM. Evaluation of the antioxidant activity of Syzygium cumini leaves. Molecules. 2008; 13(10):2545-56 https://doi.org/10.3390/molecules13102545
22. Ahmed R, Tariq M, Hussain M, Andleeb A, Masoud MS, Ali I, Mraiche F, Hasan A. Phenolic contents-based assessment of therapeutic potential of Syzygium cumini leaves extract. PloS one 2019; 14(8):e0221318 https://doi.org/10.1371/journal.pone.0221318
23. Aqil F, Gupta A, Munagala R, Jeyabalan J, Kausar H, Sharma RJ Antioxidant and antiproliferative activities of anthocyanin/ ellagitannin-enriched extracts from Syzygium cumini L.(Jamun, the Indian Blackberry). Nutrition and Cancer 2012; 64(3):428-38 https://doi.org/10.1080/01635581.2012.657766
24. Ayyappan P, Ganesan K, Jayakumararaj R Ethnobotanic information on uncommon anti-diabetic medicinal plants from Alagarkoil Forest Reserve: Evidence based strategic rationale in management of diabetics. Int J Pharm Res 2019; 16:515-26
25. Ramya S, Neethirajan K, Jayakumararaj R. Profile of bioactive compounds in Syzygium cumini-a review. J. Pharm. Res 2012; 5(8):4548-4553
26. Loganathan T, Barathinivas A, Soorya C, Balamurugan S, Nagajothi TG, Jayakumararaj R. GCMS Profile of Bioactive Secondary Metabolites with Therapeutic Potential in the Ethanolic Leaf Extracts of Azadirachta indica¬: A Sacred Traditional Medicinal Plant of INDIA. Journal of Drug Delivery and Therapeutics. 2021; 11(4-S):119-26. https://doi.org/10.22270/jddt.v11i4-S.4967
27. Soorya C, Balamurugan S, Basha AN, Kandeepan C, Ramya S, Jayakumararaj R. Profile of Bioactive Phyto-compounds in Essential Oil of Cymbopogon martinii from Palani Hills, Western Ghats, INDIA. Journal of Drug Delivery and Therapeutics. 2021; 11(4):60-5. https://doi.org/10.22270/jddt.v11i4.4887
28. Soorya C, Balamurugan S, Ramya S, Neethirajan K, Kandeepan C, Jayakumararaj R. Physicochemical, ADMET and Druggable properties of Myricetin: A Key Flavonoid in Syzygium cumini that regulates metabolic inflammations. Journal of Drug Delivery and Therapeutics. 2021 Jul 15; 11(4):66-73 https://doi.org/10.22270/jddt.v11i4.4890
29. Sabitha, M., Krishnaveni, K., Murugan, M., Basha, A.N., Pallan, G.A., Kandeepan, C., Ramya, S. and Jayakumararaj, R., In-silico ADMET predicated Pharmacoinformatics of Quercetin-3-Galactoside, polyphenolic compound from Azadirachta indica, a sacred tree from Hill Temple in Alagarkovil Reserve Forest, Eastern Ghats, INDIA. Journal of Drug Delivery and Therapeutics, 2021; 11(5-S):77-84 https://doi.org/10.22270/jddt.v11i5-S.5026
30. Loganathan T, Barathinivas A, Soorya C, Balamurugan S, Nagajothi TG, Ramya S, Jayakumararaj R. Physicochemical, Druggable, ADMET Pharmacoinformatics and Therapeutic Potentials of Azadirachtin-a Prenol Lipid (Triterpenoid) from Seed Oil Extracts of Azadirachta indica A. Juss. Journal of Drug Delivery and Therapeutics. 2021; 11(5):33-46. https://doi.org/10.22270/jddt.v11i5.4981
31. Kandeepan C, Kalaimathi RV, Jeevalatha A, Basha AN, Ramya S, Jayakumararaj R. In-silico ADMET Pharmacoinformatics of Geraniol (3, 7-dimethylocta-trans-2, 6-dien-1-ol)-acyclic monoterpene alcohol drug from Leaf Essential Oil of Cymbopogon martinii from Sirumalai Hills (Eastern Ghats), INDIA. Journal of Drug Delivery and Therapeutics. 2021; 11(4-S):109-18. https://doi.org/10.22270/jddt.v11i4-S.4965
32. Liu, R., and A. Wallqvist. Merging applicability domains for in silico assessment of chemical mutagenicity. Journal of Chemical Information and Modeling. 2014; 54(3):793-800 https://doi.org/10.1021/ci500016v
33. Liu, R., G. Tawa, and A. Wallqvist. Locally weighted learning methods for predicting dose-dependent toxicity with application to the human maximum recommended daily dose. Chemical Research in Toxicology. 2012; 25(10):2216-2226 https://doi.org/10.1021/tx300279f
34. Liu, R., P. Schyman, and A. Wallqvist. Critically assessing the predictive power of QSAR models for human liver microsomal stability. Journal of Chemical Information and Modeling. 2015; 55(8):1566-1575 https://doi.org/10.1021/acs.jcim.5b00255
35. Schyman P., R. Liu, V. Desai, and A. Wallqvist. vNN web server for ADMET predictions. Frontiers in Pharmacology. 2017 December 4; 8:889 https://doi.org/10.3389/fphar.2017.00889
36. Seeram NP, Lee R, Heber D. Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clinica Chimica Acta. 2004 Oct 1; 348(1-2):63-8. https://doi.org/10.1016/j.cccn.2004.04.029
37. Dharani J, Ravi S. in silico ADMET Screening of Compounds Present in Cyanthillium cinereum (L.) H. Rob. Asian Journal of Chemistry. 2020; 32(6):1421-6. https://doi.org/10.14233/ajchem.2020.22569
38. Mohanraj K, Karthikeyan BS, Vivek-Ananth RP, Chand RB, Aparna SR, Mangalapandi P, Samal A. IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry and Therapeutics. Scientific Reports. 2018; 8(1):1-7. https://doi.org/10.1038/s41598-018-22631-z
39. Liu T, Oprea T, Ursu O, Hasselgren C, Altman RB. Estimation of maximum recommended therapeutic dose using predicted promiscuity and potency. Clinical and translational science. 2016 Dec; 9(6):311-20. https://doi.org/10.1111/cts.12422
40. Schyman, P., R. Liu, and A. Wallqvist. General purpose 2D and 3D similarity approach to identify hERG blockers. Journal of Chemical Information and Modelling. 2016; 56(1):213-222 https://doi.org/10.1021/acs.jcim.5b00616
41. Plonka W, Stork C, Šícho M, Kirchmair J. CYPlebrity: Machine learning models for the prediction of inhibitors of cytochrome P450 enzymes. Bioorganic & Medicinal Chemistry. 2021; 46:116388. https://doi.org/10.1016/j.bmc.2021.116388
42. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports. 2017 Mar 3; 7(1):1-3. https://doi.org/10.1038/srep42717
43. Daina A, Zoete V. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 2016 Jun 6; 11(11):1117. https://doi.org/10.1002/cmdc.201600182
44. Li, D., L. Chen, Y. Li, S. Tian, H. Sun, and T. Hou. ADMET evaluation in drug discovery. 13. Development of in Silico prediction models for P-Glycoprotein substrates. 2014; 11(3):716-726 https://doi.org/10.1021/mp400450m
45. Broccatelli, F., E. Carosati, A. Neri, M. Frosini, L. Goracci, T. Oprea, and G. Cruciani. A novel approach for predicting P-Glycoprotein (ABCB1) inhibition using molecular interaction fields. 2011; 54(6):1740-1751. https://doi.org/10.1021/jm101421d
46. Chen, L., Y. Li, Q. Zhao, H. Peng, and T. Hou. ADME evaluation in drug discovery. 10. Predictions of P-Glycoprotein inhibitors using recursive partitioning and naive bayesian classification techniques. 2011; 8(3):889-900 https://doi.org/10.1021/mp100465q
47. Schyman, P., R. Liu, and A. Wallqvist. Using the variable-nearest neighbour method to identify P-glycoprotein substrates and inhibitors. ACS Omega. 2016; 1(5):923-929 https://doi.org/10.1021/acsomega.6b00247
48. Attene-Ramos, M., R. Huang, S. Michael, K. Witt, A. Richard, R. Tice, A. Simeonov, C. Austin, M. Xia. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. 2015; 123(1):49. https://doi.org/10.1289/ehp.1408642
49. Naef R. A generally applicable computer algorithm based on the group additivity method for the calculation of seven molecular descriptors: Heat of combustion, LogPO/W, LogS, refractivity, polarizability, toxicity and LogBB of organic compounds; scope and limits of applicability. Molecules 2015; 20(10):18279-351 https://doi.org/10.3390/molecules201018279
50. Zhou Y, Wu F, Li L, Shen X, Chen G, Wang X, Liang X, Tan M, Huang Z. Computational approaches in preclinical studies on drug discovery and development. Frontiers in Chemistry. 2020; 8:726-31. https://doi.org/10.3389/fchem.2020.00726
51. Kong M, Xie K, Lv M, Li J, Yao J, Yan K, Wu X, Xu Y, Ye D. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise. Biomedicine & Pharmacotherapy. 2021; 133:110975. https://doi.org/10.1016/j.biopha.2020.110975
52. Alfei S, Marengo B, Zuccari G. Oxidative stress, antioxidant capabilities, and bioavailability: Ellagic acid or urolithins?. Antioxidants. 2020 Aug; 9(8):707. https://doi.org/10.3390/antiox9080707
Statistics
196 Views | 207 Downloads
How to Cite
1.
Ramya S, Murugan M, Krishnaveni K, Sabitha M, Kandeepan C, Jayakumararaj R. In-silico ADMET profile of Ellagic Acid from Syzygium cumini: A Natural Biaryl Polyphenol with Therapeutic Potential to Overcome Diabetic Associated Vascular Complications. JDDT [Internet]. 15Jan.2022 [cited 19May2022];12(1):91-01. Available from: http://jddtonline.info/index.php/jddt/article/view/5179

Most read articles by the same author(s)