J. Pharm. Technol. Res. Manag.

Molecular Docking Studies of Phenolic Compounds from Syzygium cumini with Multiple Targets of Type 2 Diabetes

Ajmer Singh Grewal, Neelam Sharma, Sukhbir Singh, Sandeep Arora

KEYWORDS

Alpha-glucosidase, Dipeptidyl peptidase 4, Glucagon receptor, Glucokinase, Glycogen synthase kinase 3, Phenolic compounds, Syzygium cumini.

PUBLISHED DATE Nov. 2, 2018
PUBLISHER The Author(s) 2018. This article is published with open access at www.chitkara.edu.in/publications.
ABSTRACT

Treatment of type 2 diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Syzygium cumini is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. It contains various types of chemical constituents including terpenoids, tannins, anthocyanins, flavonoids and other phenolic compounds. Some flavonoids and other phenolic compounds from S. cumini were reported in literature to have type 2 antidiabetic potential. The main objective of the current investigation was in silico screening of some phenolic compounds from S. cumini against multiple targets associated with type 2 diabetes to explore the mechanism of antidiabetic action and prediction of binding mode using molecular docking studies. In silico docking studies were performed for the selected molecules in the binding site of multiple targets associated with type 2 diabetes (α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, glucokinase and glucagon receptor). Amongst the compounds tested in silico, rutin showed appreciable binding with multiple targets of type 2 diabetes including α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, and glucagon receptor. Catechin was found to inhibit both α-glucosidase, and dipeptidyl peptidase 4. This information can be utilized for the design and development of potent multi-functional candidate drugs with minimal side effects for type 2 diabetes therapeutics.

INTRODUCTION

Diabetes mellitus (or simply diabetes) is a long-lasting disorder of food metabolism characterized by hyperglycemia, originating due to defect in insulin secretion, insulin function or both leading to tissue and vascular damage and resulting in a variety of complications (Bastaki, 2005; Cade, 2008; Grewal et al., 2014; Grewal et al., 2016). It is currently one of the largest global health emergencies; according to the International Diabetes Federation, in 2017 there were 425 million adults estimated to have diabetes, and the number is likely to reach 629 million by 2045 (IDF). Type 2 diabetes (T2D) affecting more than 90% of all the diabetic patients, is a long-term disordered food metabolism caused by declined insulin action (Kohei, 2010; Olokoba et al., 2012). Although a variety of medicines are available for T2D therapeutics, no single drug is useful for achieving long-term control of normal blood glucose levels in majority of patients. Due to this reason, general practitioners prescribe combination of antidiabetic agents for T2D therapy and overdose of antidiabetic medicines could lead to severe hypoglycemia resulting in brutal toxic and side effects. This caused the scientific community to search for new antidiabetic drugs (Olokoba et al., 2012; Osadebe et al., 2014). Large numbers of plants and parts of plants were reported with their antidiabetic properties. Various types of plant-derived active principles representing several bioactive compounds have established their beneficial role for possible use in T2D therapeutics (Patil et al., 2011; Ibrahim et al., 2013; Kumar et al., 2012). Syzygium cumini (Linn.) is an economically important tropical fruit tree belonging to the family Myrtaceae largely grown in Indian subcontinent along with some other parts of South Asia including Bangladesh, Sri Lanka, Nepal, Pakistan, Burma and Indonesia. It is also cultivated in some parts of Africa and South America (Swami et al., 2012; Srivastava and Chandra, 2013). It is commonly known as jamun in India, black plum in Europe, jambolan in Spanish spoken countries, and Jambolac in Brazil. It is also known as java plum, Indian blackberry, Portuguese plum, Malabar plum, purple plum, Jamaica and damson plum (Ayyanar and Subash-Babu, 2012; Chagas et al., 2015). Various types of secondary metabolites like flavonoids (quercetin, rutin, catechin, kaempferol, myricetin, isoquercetin, myricetin deoxyhexoside, myricetin-3-L-arabinoside, dihydromyricetin, quercetin-3-D-galactoside, myricetin 3-O-β-D-glucuronopyranoside, myricetin-4’-methylether 3-O-α-rhamnopyranoside), phenolic acids (caffeic acid, chlorogenic acid, ellagic acid, Ferulic acid, gallic acid, 3,3’-di-O-methyl ellagic acid,3,3’,4-tri-O-methyl ellagic acid), tannins (nilocetin Corilagin, 3,6-HHDP glucose, 4,6-HHDP glucose, 1-galloyl glucose, 3-galloyl glucose, HHDP-galloyl glucose, trigalloyl glucose, Eugenol, and oleanolic acid), terpenes (α-pinene, α-cadinol, pinocarvone, pinocarveol, α-terpeneol, myrtenol, eucarvone, muurolol, myrtenal, cineole, geranyl acetone, β-pinene, β-terpinene, betulinic acid, eugenol, citronellol, geraniol, hotrienol, nerol, β-phenylethanol, phenylpropanal, β-siterol, and friedelin), anthocyanins (Cyanidin, delfinidin and petudinin), alkaloids (jambosine), glycosides (jamboline and antimelin), minerals (Ca, Mg, Na, K, and Cu), vitamins (thiamine, riboflavin, and nicotinic acid) are present in different parts of the plant (Veigas et al., 2007; Ramya et al., 2012; Ayyanar and Subash-Babu, 2012; Chagas et al., 2015; Bijauliya et al., 2017). S. cumini is known to possess wide range of pharmacological and therapeutic properties, which have been attributed to the presence of bioactive compounds in different parts of the plant (Srivastava and Chandra, 2013). A variety of various pharmacological activities were shown by S. cumini including anti-diabetic (Kumar et al., 2008, Tripathi and Kohli, 2014), anti-cancer (Afify et al., 2011), anti-oxidant (Nair et al., 2013), antibacterial/antimicrobial (Prateek et al., 2015), anti-inflammatory (Muruganandan et al., 2001), anti-diarrhoeal (Shamkuwar et al., 2012), antiviral (Sood et al., 2012), cardio-protective (Herculano et al., 2014), anticonvulsant (Kumar et al., 2007), antinociceptive (Avila-Pena et al., 2007), gastro-protective (Chaturvedi et al., 2009), anti-fertility (Rajasekaran et al., 1998), chemoprotective (Goyal et al., 2010), anti-allergic (Brito et al., 2007), inhibition of lipid peroxidation (Veigas et al., 2007), anti-histaminic (Mahapatra et al., 1986), anti-pyretic (Mahapatra et al., 1986), anti-plaque (Namba et al., 1985), anti-hyperlipidemic (Chagas et al., 2015) and hepatoprotective activity (Veigas et al., 2008). Some flavonoids and other phenolic derivatives obtained from S. cumini including quercetin, myricetin, kaempferol, ferulic acid, ellagic acid, catechin and rutin were reported in literature to have type 2 antidiabetic potential (Haraguchi et al., 1998; Ohnishi et al., 2004; Kamalakkannan and Prince, 2006; Liu et al., 2007; Sharma et al., 2008; Esmaeili et al., 2009; Wein et al., 2010; Bardy et al., 2013; Chagas et al., 2015). Currently, medicinal chemistry research is focussed on polypharmacological compounds acting on multiple targets against complex disorders including diabetes, neoplastic diseases, neurodegenerative disorders, and certain infectious disorders owing to superior efficacy, better safety profile, and ease of administration of multi-target drugs. Molecular docking is one of the most widely used techniques for the design of multi-target drugs (EspinozaFonseca, 2006; Scotti et al., 2017; Ramsay et al., 2018). In the current investigation docking studies were performed for some phenolic compounds obtained from S. cumini (Figure 1) in the binding site of multiple targets associated with T2D (α-glucosidase (AG), dipeptidyl peptidase 4 (DPP4), glycogen synthase kinase 3 (GSK3), glucokinase (GK) and glucagon receptor (GCR)) in order to explore the mechanism of antidiabetic action and binding modes using molecular docking studies.

Page(s) 125-133
URL http://dspace.chitkara.edu.in/jspui/bitstream/123456789/790/1/JPTRM%206-2-3.pdf
ISSN Print : 2321-2217, Online : 2321-2225
DOI 10.15415/jptrm.2018.62009
CONCLUSION

Molecular docking studies using AutoDock vina and AutoDock Tools was performed to explore the binding mechanism of the selected natural phenolic compounds from S. cumini with multiple targets associated with T2D. In current in silico docking study, results clearly demonstrated that amongst the compounds tested in silico, rutin showed appreciable binding with multiple targets of T2D including α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, and glucagon receptor. Catechin was found to inhibit both α-glucosidase, and dipeptidyl peptidase 4. Myricetin was found to inhibit AG and quercetin was found to inhibit DPP4. Kaempferol was found to activate allosterically GK protein. In silico study is actually an added advantage to screen the type 2 antidiabetic agents and natural phenolic compounds may serve as useful leads for the synthesis of clinically useful and safe type 2 antidiabetic agents. However, structural modifications and further studies on these natural phenolic compounds are required to develop safe and potent natural type 2 antidiabetic agents.

REFERENCES
  • Afify, A.M.R., Fayed, F.A., Shalaby, E.A., and ElShemy, H.A. (2011) Syzygium cumini (pomposia) active principles exhibit potent anticancer and antioxidant activities. African Journal of Pharmacy and Pharmacology, 5(7), 948–956.
  • Avila-Pena, D., Pena, N., Quintero, S.L., and Suarez-Roca, H. (2007) Antinociceptive activity of Syzygium jambos leaves extract on rats. Journal of Ethnopharmacology, 112(2): 380–385. https://doi.org/10.1016/j.jep.2007.03.027
  • Ayyanar, M., and Subash-Babu, P. (2012) Syzygium cumini (L.) Skeels: a review of its phytochemical constituents and traditional uses. Asian Pacific Journal of Tropical Biomedicine, 2, 240–246. https://doi.org/10.1016/S2221-1691(12)60050-1
  • Bardy, G., Virsolvy, A., Quignard, J., Ravier, M., Bertrand, G., Dalle, S., et al. (2013) Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells. British Journal of Pharmacology, 169, 1102–1113. https://doi.org/10.1111/bph.12194
  • Bastaki, S. (2005) Diabetes mellitus and its treatment. International Journal of Diabetes Metabolism, 13, 111–134.
  • Bijauliya, R.K., Alok, S., Singh, M., and Mishra, S.B. (2017) Morphology, phytochemistry and pharmacology of Syzygium cumini (Linn.) - an overview. International Journal of Pharmaceutical Sciences and Research, 8(6), 2360–2371.
  • Brito, F.A., Lima, L.A., Ramos, M.F., Nakamura, M.J., Cavalher-Machados, S.C., Henrigues, M.G., et al. (2007) Pharmacological study of anti-allergic activity of Syzygium cumini (L) Skeels. Brazillian Journal of Medical and Biological Research, 40, 105–115. https://doi.org/10.1590/S0100-879X2007000100014
  • Cade, W.T. (2008) Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Physical Therapy, 88, 1322–1335. https://doi.org/10.2522/ptj.20080008
  • Chagas, V.T., França, L.M., Malik, S., and Paes, A.M.A. (2015) Syzygium cumini (L.) skeels: a prominent source of bioactive molecules against cardiometabolic diseases. Frontiers in Pharmacology, 6, Article 259. https://doi.org/10.3389/fphar.2015.00259
  • Charaya, N., Pandita, D., Grewal, A.S., and Lather, V. (2018) Design, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators. Computational Biology and Chemistry, 73, 221–229. https://doi.org/10.1016/j.compbiolchem.2018.02.018
  • Chaturvedi, A., Bhawani, G., Agarwal, P.K., Goel, S., Singh, A., and Goel, R.K. (2009) Ulcer healing properties of ethanolic extract of Eugenia jambolana seed in diabetic rats : study on gastric mucosal defensive factors. Indian Journal of Physiology and Pharmacology, 53, 16–24.
  • Esmaeili, M.A., Zohari, F., and Sadeghi, H. (2009) Antioxidant and protective effects of major flavonoids from Teucriumpolium on beta-cell destruction in a model of streptozotocin-induced diabetes. Planta Medica, 75, 1418–1420. https://doi.org/10.1055/s-0029-1185704
  • Espinoza-Fonseca, L.M. (2006) The benefits of the multi-target approach in drug design and discovery. Bioorganic & Medicinal Chemistry, 14(4), 896–897. https://doi.org/10.1016/j.bmc.2005.09.011
  • Goyal, P.K., Verma, P., Sharma, P., Parmar, J., and Agarwal, A. (2010) Evaluation of anti-cancer and anti-oxidative potential of Syzygium cumini against benzo[a]pyrene (BaP) induced gastric carcinogenesis in mice. Asian Pacific Journal of Cancer Prevention, 11, 753–758.
  • Grewal, A.S., Sekhon, B.S., and Lather, V. (2014) Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. Mini Reviews in Medicinal Chemistry, 14(7), 585–602. https://doi.org/10.2174/1389557514666140722082713
  • Grewal, A.S., Bhardwaj, S., Pandita, D., Lather, V., and Sekhon, B.S. (2016) Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Reviews in Medicinal Chemistry, 16, 120–162. https://doi.org/10.2174/1389557515666150909143737
  • Grewal, A.S., Lather, V., Pandita, D., and Bhayana, G. (2017) Synthesis, docking and biological evaluation of phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPARδ agonists. Letters in Drug Design and Discovery, 14(11), 1239–1251. https://doi.org/10.2174/1570180814666170327164 443
  • Haraguchi, H., Kanada, M., Fukuda, A., Naruse, K., Okamura, N., and Yagi, A. (1998) An inhibitor of aldose reductase and sorbitol accumulation from Anthocepharus chinensis. Planta Medica, 64, 68–69. https://doi.org/10.1055/s-2006-957369
  • Herculano, E.D.A., Costa, C.D.F., Rodrigues, A.K.B.F., Junior, J.X.A., Santana, A.E.G., França, P.H.B., et al. (2014) Evaluation of cardiovascular effects of edible fruits of Syzygium cumini Myrtaceae (L) skeels in rats. Tropical Journal of Pharmaceutical Research, 13(11), 1853–1861. https://doi.org/10.4314/tjpr.v13i11.12
  • International Diabetes Federation. Available at: https://www.idf.org/e-library/epidemiology-research/ diabetes-atlas/134-idf-diabetes-atlas-8th-edition.html (Accessed 10 July 2018).
  • Kamalakkannan, N., and Prince, P.S.M. (2006) Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic Wistar rats. Basic and Clinical Pharmacology and Toxicology, 98, 97–103. https://doi.org/10.1111/j.1742-7843.2006.pto_241.x
  • Kohei, K. (2010) Pathophysiology of type 2 diabetes and its treatment policy. Japan Medical Association Journal, 53, 41–46.
  • Kumar, A., Padmanabhan, N. and Krishnan, M.R.V. (2007) Central Nervous system activity of Syzygium cumini seed. Pakistan Journal of Nutrition, 6(6), 698–700. https://doi.org/10.3923/pjn.2007.698.700
  • Kumar, R., Jayachandran, T., Deecaraman, M., Aravindan, P., Padmanabhan, N., and Krishan, M.R.V. (2008) Anti-diabetic activity of Syzygium cumini and its isolated compound against streptozotocin-induced diabetic rats. Journal of Medicinal Plants Research, 2(9), 246–249.
  • Kumar, S., Saini, M., Kumar, V., Prakash, O., Arya, R, Rana, M., et al. (2012) Traditional medicinal plants curing diabetes: a promise for today and tomorrow. Asian Journal of Traditional Medicines, 7, 178–188.
  • Lagorce, D., Bouslama, L., Becot, J., Miteva, M.A., and Villoutreix, B.O. (2017) FAF-Drugs4: free ADMEtox filtering computations for chemical biology and early stages drug discovery. Bioinformatics, 33(22), 3658–3660. https://doi.org/10.1093/bioinformatics/btx491
  • Liu, I.-M., Tzeng, T.-F., Liou, S.-S., and Lan, T.-W. (2007) Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a highfructose diet in rats. Life Sciences, 81, 1479–1488. https://doi.org/10.1016/j.lfs.2007.08.045
  • Mahapatra, P.K., Chakraborty, D., and Chaudhari, A.K.N. (1986) Anti-inflammatory and antipyretic activities of Syzygium cumini. Planta Medica, 6, 540. https://doi.org/10.1055/s-2007-969339
  • Miteva, M.A., Violas, S., Montes, M., Gomez, D., Tuffery, P., and Villoutreix, B.O. (2006) FAF-Drugs: free ADME/tox filtering of compound collections. Nucleic Acids Research, 34, W738–W744. https://doi.org/10.1093/nar/gkl065
  • Miteva, M.A., Guyon, F., and Tufféry, P. (2010) Frog2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Research, 38, W622–627. https://doi.org/10.1093/nar/gkq325
  • Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., et al. (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Journal of Computational Chemistry, 16, 2785–2791. https://doi.org/10.1002/jcc.21256
  • Muruganandan, S., Srinivasan, K., Chandra, S., Tandan, S.K., Lal, J., and Raviprakash, V. (2001) Anti-inflammatory activity of Syzygium cumini bark. Fitoterapia, 72(4), 369–375. https://doi.org/10.1016/S0367-326X(00)00325-7
  • Nair, L.K., Begum, M., and Geetha, S. (2013) In vitro-antioxidant activity of the seed and leaf extracts of Syzygium cumini. IOSR Journal of Environmental Science, Toxicology and Food Technology, 7(1), 54-62. https://doi.org/10.9790/2402-0715462
  • Namba, T., Tsunezuka, M., Dissanayake, D.M.R.B., Upali, P., Keiko, S., Nobuko, K., el al. (1985) Studies on dental caries prevention by traditional medicines part VII, screening of Ayurvedic medicines for antiplaque action. Japanese Journal of Pharmacognosy, 39(2), 146–153.
  • Ohnishi, M., Matuo, T., Tsuno, T., Hosoda, A., Nomura, E., Taniguchi, H., et al. (2004) Antioxidant activity and hypoglycemic effect of ferulic acid in STZinduced diabetic mice and KK-Ay mice. Biofactors, 21(1-4), 315–319. https://doi.org/10.1002/biof.552210161
  • Olokoba, A.B., Obateru, O.A., and Olokoba, L.B. (2012) Type 2 diabetes mellitus: a review of current trends. Oman Medical Journal, 27, 269–273. https://doi.org/10.5001/omj.2012.68
  • Osadebe, P.O., Odoh E.U., and Uzor, P.F. (2014) Natural products as potential sources of antidiabetic drugs. British Journal of Pharmaceutical Research, 4(17), 2075–2095. https://doi.org/10.9734/BJPR/2014/8382
  • Patil, R., Patil, R., Ahirwar, B., and Ahirwar, D. (2011) Current status of Indian medicinal plants with antidiabetic potential: a review. Asian Pacific Journal of Tropical Biomedicine, 1(2), S291–S298. https://doi.org/10.1016/S2221-1691(11)60175-5
  • Prateek, A., Meena, R.K., and Yadav, B. (2015) Antimicrobial activity of Syzygium cumini. Indian Journal of Applied Research, 5(9), 63–66.
  • Rajasekaran, M., Bapana, J.S., Lakshmanan, A.G., Nair, R., Veliath, A.J., and Panchanadam, M. (1998) Antifertility effect in male rats of oleanolic acid, a triterpene from Eugenia jambolana flowers. Journal of Ethnopharmacology, 24, 115–121. https://doi.org/10.1016/0378-8741(88)90142-0
  • Ramsay, R.R., Popovic-Nikolic, M.R., Nikolic, K., Uliassi, E., and Bolognesi, M.L. (2018) A perspective on multi-target drug discovery and design for complex diseases. Clinical and Translational Medicine, 7(1), 3. https://doi.org/10.1186/s40169-017-0181-2
  • Ramya, S., Neethirajan, K., and Jayakumararaj, R. (2012) Profile of bioactive compounds in Syzygium cumini-a review. Journal of Pharmacy Research, 5, 4548–4553.
  • Rizvi, S.I., and Mishra, N. (2013) Traditional Indian medicines used for the management of diabetes mellitus. Journal of Diabetes Research, 2013, Article ID 712092. https://doi.org/10.1155/2013/712092
  • Scotti, L., Mendonca, F.J. Jr., Ishiki, H.M., Ribeiro, F.F., Singla, R.K., Barbosa Filho, J.M., et al. (2017) Docking Studies for Multi-Target Drugs. Current Drug Targets, 18(5), 592–604. https://doi.org/10.2174/1389450116666150825111818
  • Shamkuwar, Prashant, B., Pawar, D.P., and Chauhan, S.S. (2012) Antidiarrhoeal activity of seeds of Syzygium cumini L. Journal of Pharmacy Research, 5(12), 5537.
  • Sharma, B., Viswanath, G., Salunke, R., and Roy, P. (2008) Effects of flavonoid-rich extract from seeds of Eugenia jambolana (L.) on carbohydrate and lipid metabolism in diabetic mice. Food Chemistry, 110, 697–705. https://doi.org/10.1016/j.foodchem.2008.02.068
  • Sood, R., Swarup, D., Bhatia, D., Kulkarni, D.D., Dey, S., Saini, M., et al. (2012) Antiviral activity of crude extracts of Eugenia jambolana Lam. against highly pathogenic avian influenza (H5N1) virus. Indian Journal of Experimental Biology, 50, 179–218.
  • Srivastava, S., and Chandra, D. (2013). Pharmacological potentials of Syzygium cumini: a review. Journal of the Science of Food and Agriculture, 93, 2084–2093. https://doi.org/10.1002/jsfa.6111
  • Swami, S.B., Thakor, N.S., Patil, M.M., and Haldankar, P.M. (2012) Jamum (Syzygium cumini (L.)): a review of its food and medicinal uses. Food and Nutrition Sciences, 3(8), 1100–1117. https://doi.org/10.4236/fns.2012.38146
  • Tripathi, A.K., and Kohli, S. (2014) Pharmacognostical standardization and antidiabetic activity of Syzygium cumini (Linn.) barks (Myrtaceae) on streptozotocininduced diabetic rats. Journal of Complementary and Integrative Medicine, 11(2), 71–81. https://doi.org/10.1515/jcim-2014-0011
  • Trott, O., and Olson, A.J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry, 31, 455–461.
  • Veigas, J.M., Narayan, M.S., Laxman, P.M., and Neelwarne, B. (2007) Chemical nature stability and bioefficacies of anthocyanins from fruit peel of Syzygium cumini Skeels. Food Chemistry, 105, 619–627. https://doi.org/10.1016/j.foodchem.2007.04.022
  • Veigas, J.M., Shrivasthava, R., and Neelwarne, B. (2008) Efficient amelioration of carbon tetrachloride induced toxicity in isolated rat hepatocytes by Syzygium cumini Skeels extract. Toxicology In vitro, 2008; 22, 1440–1446. https://doi.org/10.1016/j.tiv.2008.04.015
  • Wein, S., Behm, N., Petersen, R.K., Kristiansen, K., and Wolffram, S. (2010) Quercetin enhances adiponect in secretion by a PPAR-gamma independent mechanism. European Journal of Pharmaceutical Sciences, 41, 16–22. https://doi.org/10.1016/j.ejps.2010.05.004