IN SILICO MOLECULAR DOCKING OF ANTIDIABETIC AGENTS FROM MEDICINAL PLANTS OF BANGLADESH AGAINST GLYCOGEN SYNTHASE KINASE

 

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ABOUT AUTHORS
Nazmul Islam Prottoy*, Aisha Siddiqua Boby, Md. Asad Ullah, Bishajit Sarkar1, Sohana Hossain
Dept. of Biotechnology and Genetic Engineering
Jahangirnagar University, Savar, Dhaka-1342, Bangladesh

ABSTRACT
Diabetes Mellitus (DM) is a metabolic disorder which affects the people of all groups around the world. Although medication is available in the market but plant derived compounds are often preferable to everyone due to their less toxicity and side effects. This study has been designed to investigate the interaction between medicinal plant derived antidiabetic agents (Arjunic acid, Quercetin and Gallic Acid) and regulatory target enzyme, Glycogen Synthase Kinase-3 Beta (GSK3B). Quercetin showed the strong interaction with the target molecule among the all compounds. However, further in vitro study is required to find out the best remedy of diabetes.

Reference Id: PHARMATUTOR-ART-2672

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 7, Issue 07

Received On: 26/05/2019; Accepted On: 20/06/2019; Published On: 01/07/2019

How to cite this article: Prottoy, N., Boby, A., Sarkar, B., Ullah, A. and Hossain, S. 2019. In Silico Molecular Docking of Antidiabetic Agents from Medicinal Plants of Bangladesh against Glycogen Synthase Kinase. PharmaTutor. 7, 7 (Jul. 2019), 18-20

INTRODUCTION
Diabetes is a metabolic disease characterized by hyperglycemia resulting from defects in pancreatic insulin secretion, insulin action, or combination of both. The chronic diabetes is the major cause of dysfunction of organs like eyes, kidneys, nerves, heart, and blood vessels (ADA, 2014). The total number diabetes patient has increased drastically from 180 million in 1980 to 422 million in 2014. The prevalence of patient has increased doubly in past three decades from 4.7% to 8.5% globally. Recent studies have indicated that the occurrence of the disease is now approximately similar in both low income and high income countries (Roglic, 20016).

Many medicinal plants have been reported to have antidiabetic activity in laboratory experiments (Tapsell et al. 2006). Bangladesh is an agricultural country and many plant species are available here, and a good portion among them is effective in healing diabetes. Plan species like Terminalia arjuna, Terminalia bellirica and Psidium guajava are widely used as ayurvedic regimen by the prople of rural areas in Bangladesh (Rahmatullah et al., 2010). Arjunic acid from Terminalia arjuna, Gallic acid from Terminalia bellirica, and Quercetin from Psidium guajava have been shown to be effective in alleviating diabetes in earlier in vitro study (Morshed et al., 2011; Sabu and Kuttan, 2009; Cheng et al., 2009).

GSK3B is an enzyme that phosphorylates Glycogen Synthase (GS) and pushes it into an inactivated form depending on the insulin release in the body. So, whenever GSK3b is bound with a molecule in its active site, it can’t phosphorylate Glycogen Synthase anymore. And Glycogen Synthase in turn produces glycogen from glucose inside the body and keeps glucose concentration lower (Rayasam et al., 2009).

The DOCKING program explores possible orientations of a molecule within a macromolecular active site by superimposing atoms onto precomputed site points of a target protein. By varying the amount of sampling, the program monitors the time convergence of scores and rankings which can be analyzed to find the best ligand for the target protein (Ewing and Kuntz, 1997).

In our in silico study, we found Quercetin as the best inhibitor of GSK3B.

MATERIALS
UCSF Chimera, alpha version 1.14 (Pettersen et al., 2004) has been used for the preparation of molecules and grid generation, Discovery Studio Visualizer (BioVia, 2015)  has been used for the visualization of the target and ligand, and Autodock Vina (Morris et al., 2009) has been used for carrying out the docking.

METHOD
Ligand Preparation
Arjunic acid (CID: 15385516), Gallic acid (CID: 370) and Quercetin (CID: 5280343) were downloaded from PubChem in sdf format. Then the structures were converted into PDB format using DS Studio. PDB file of one ligand was opened in Chimera and then the structure was minimized and hydrogen was added. Finally, Gastiger Charge was applied and the minimized ligand was saved. The similar procedure was also applied for other remaining structures.

Receptor Preparation
The 3D structure of GSK3B (PDB 1H8F) was downloaded from Protein Data Bank in PDB format (Dajani et al., 2001). One chain of the dimeric protein and all the water molecules were deleted. Hydrogen and Gastiger charges were applied. Then the receptor molecule was saved in repository.

Receptor Grid Preparation and Docking
Receptor grid is constructed to tie the active site of the receptor within the matrix. This grid allows the ligand to find the active site of the target protein easily. Receptor grid was generated keeping default parameters. A cubic box of search volume size of 15×15×15 was built around the active site of the target. Each of the ligand molecules was loaded and docking was performed using synchronised AutoDock Vina.

Result
In order to study the interaction of three isolated antidiabetic compounds- Arjunic acid (CID: 15385516), Gallic acid (CID: 370) and Quercetin (CID: 5280343)   from medicinal plants with a metabolic enzyme we performed the in silico study. Quercetin showed the lowest negative docking score which means that, this compound is most favorable for interacting with the active site of Glycogen Synthase Kinase-3 Beta.

Table 1: Docking score of different ligands against Glycogen Synthase Kinase-3 Beta.

Figure 1: 3D representation of ligand interaction- (A) Arjunic Acid, (B) Gallic Acid, (C) Quercetin in the active site of Glycogen Synthase Kinase-3 Beta (PDB 1H8F)

DISCUSSION
The docking scores of different ligand have been represented in Table 1 and the 3D representation of the interaction between ligand and receptor has been depicted in Figure 1. Quercetin has higher affinity for binding in the active site of GSK3B. This binding prevents GSK3B from inactivating Glycogen Synthase. As a result, the activated Glycogen Synthase produces more glycogen using the free glucose in the bloodstream and stores glycogen in the liver. This mechanism ultimately leads to the lower glucose concentration in the bloodstream.

CONCLUSION
Further in vitro study may be required to find out plant derived antidiabetic agent hopefully which will be less toxic, cheap and effective.

REFERENCES
1. ADA (2014); Diagnosis and classification of diabetes mellitus; American Diabetes Association.   Diabetes Care; 37; S81-S90.
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3. Cheng FC, Shen SC, Wu JS (2009); Effect of guava (Psidium guajava L.) leaf extract on glucose uptake in rat hepatocytes; Journal of food science; 74(5); H132-8.
4. Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH (2001); Crystal structure of glycogen synthase kinase 3β: structural basis for phosphate-primed substrate specificity and autoinhibition; Cell; 105(6); 721-32.
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7. Morshed MA, Haque A, Rokeya B, Ali L (2011); Anti-hyperglycemic and lipid lowering effect of Terminalia arjuna Bark extract on Streptozotocin induced Type-2 Diabetic Model Rats;  International Journal of Pharmacy and Pharmaceutical Sciences; 3(4); 449-53.
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10. Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (2009); Glycogen synthase kinase 3: more than a namesake; British journal of pharmacology; 156(6); 885-98.
11. Roglic G (20016); WHO Global report on diabetes: A summary; Int J Non-Commun Dis;1; 3-8
12. Sabu MC, Kuttan R (2009); Antidiabetic and antioxidant activity of Terminalia belerica. Roxb; Indian journal of experimental biology; 47(4); 270-5.
13. Tapsell LC, Hemphill I, Cobiac L, Sullivan DR, Fenech M, Patch CS, Roodenrys S, Keogh JB, Clifton  PM, Williams PG, Fazio VA (2006); Health benefits of herbs and spices: the past, the present, the future; The Medical Journal of Australia; 185 (4);  S1-S24.

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