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


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

PUBLISHER The Author(s) 2018. This article is published with open access at www.chitkara.edu.in/publications.

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.


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

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.

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