Journal of Applied Pharmaceutical Science Vol.

8(04), pp 150-160, April, 2018

Available online at http://www.japsonline.com
DOI: 10.7324/JAPS.2018.8422
ISSN 2231-3354

Molecular Docking Studies Involving the Inhibitory Effect of

Gymnemic Acid, Trigonelline and Ferulic Acid, the Phytochemicals
with Antidiabetic Properties, on Glycogen Synthase Kinase 3 (α and β)

V. Roshana Devi, C. Sharmila, S. Subramanian*

Department of Biochemistry, University of Madras, Guindy Campus, Chennai - 600 025, Tamilnadu, India.

ARTICLE INFO ABSTRACT

Article history: Type 2 diabetes mellitus (T2DM) accounts for more than 90% of the diabetic population and its prevalence is linked
Received on: 09/02/2018 to obesity-induced insulin resistance followed by a relative rate of insulin secretion from the β-cells of the pancreas.
Accepted on: 18/03/2018 Several drugs are available to maintain normoglycemia in diabetic individuals through the regulation of biological
Available online: 29/04/2018 functions such as controlling the absorption of glucose in the intestine, increasing the insulin sensitivity, improvement
in the secretion of insulin, prevention of excessive breakdown of glucose as well as gluconeogenesis and enhancement
of glycogen synthesis. Since, most of the currently available drugs elicit undesirable side effects in addition to
Key words:
the development of resistance after prolonged use, the search for lead molecules preferably from plant origin still
Diabetes mellitus,
continues. Recently, we have formulated a mixture containing three phytochemicals from medicinal plants namely
phytochemicals, glycogen
Gymnemic acid, Trigonelline and Ferulic acid in the ratio of 2:3:1 and systematically evaluated its antidiabetic efficacy
synthase kinase 3, glycogen
in type 2 diabetes in rats. Glycogen metabolism plays an important role in the regulation of glucose homeostasis and
metabolism, in silico studies.
it is controlled by the two rate-limiting enzymes namely glycogen synthase and glycogen phosphorylase. The activity
of glycogen synthase is regulated by glycogen synthase kinase, a negative regulator of insulin signaling pathway.
GSK-3 subsists in two similarly associated isoforms namely GSK-3α and GSK-3β with the molecular weight of 51
kDa and 47 kDa, respectively. They possess almost indistinguishable affinities for their substrates and their biological
role. The present study is aimed to perform molecular docking studies involving the inhibitory effect of individual
phytochemicals with antidiabetic properties on Glycogen synthase kinase-3 (α & β). The binding energy obtained
for GA, TG and FA for GSK-3α is found to be −5.33, –6.85, and –7.0 Kcal/Mol, respectively. Likewise, the binding
energy calculated for GA, TG, and FA for GSK-3β is found to be –4.69, –5.51, and –5.05 Kcal/Mol, respectively.
The data obtained evidenced the inhibitory role of GTF on the activity of GSK isoforms in the regulation of glycogen
metabolism.

INTRODUCTION the molecular weight of 51 kDa and 47 kDa, respectively. They

Glycogen synthase kinase-3 is a multi-tasking cytosolic possess almost indistinguishable affinities for their substrates and
serine/threonine protein kinase, originally identified by Embi their biological role (Stambolic and Woodgett, 1994).
et al. (1980) from the rabbit skeletal muscle as a regulator of Type 2 diabetes mellitus (T2DM) accounts for more
glycogen synthase (GS). In contrast to other kinases, the action of than 90% of the diabetic population and its prevalence is linked
GSK-3 inhibits glycogen synthase activity. GSK-3 subsists in two to obesity-induced insulin resistance followed by a relative rate
similarly associated isoforms namely GSK-3α and GSK-3β with of insulin secretion from the β-cells of the pancreas. Interestingly,
the elevated activities of GSK-3 have been reported in diabetic
and obese strains of rats/mice (Eldar-Finkelman et al., 1999). The
*
Corresponding Author activity of glycogen synthase is regulated by glycogen synthase
Dr. S. Subramanian, Professor, Department of Biochemistry, University kinase, a negative regulator of insulin signaling pathway and its
of Madras, Guindy Campus, Chennai - 600 025, Tamilnadu, India. activity is implicated in various pathological conditions including
E-mail: subbus2020 @ yahoo.co.in

© 2018 V. Roshana Devi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License -NonCommercial-
ShareAlikeUnported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).
 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160 151

type 2 diabetes, malignant cells, and chronic inflammatory Molecular docking using Auto Dock
disorders. It phosphorylates and inhibits the functioning of two Auto Dock Tools were used to study the docking
key targets of the insulin pathway namely IRS-1 and glycogen simulations (Trott and Olson, 2010). Auto Dock 4.2 is used to
synthase. Insulin receptors in the peripheral tissues provoke a study the molecular interactions between the phytochemical
cascade of signaling pathways that result in the activation of Akt ligands such as Gymnemic acid, Trigonelline and Ferulic acid and
which subsequently gets phosphorylates to inhibit the activity of the enzyme receptor, glycogen synthase kinase-3.
GSK3 (Cross et al., 1995). Thus, insulin decreases the activity of Auto Dock requires pre-calculated grid maps, one for
GSK-3 (Lawlor and Alessi, 2001). GSK is also been implicated in each type of atom present in the flexible molecules being docked
ER stress in the β cells and decrease the activity of GSK thereby and its stores the potential energy arising from the interaction
protect the cells from death (Srinivasan et al., 2005). with rigid macromolecules. This grid must surround the region
The N-terminal phosphorylation of GSK-3α at Serine 21 of interest in the rigid macromolecule. The grid box size was set
and GSK-3β at Serine 9 elicits an inhibitory effect in the regulation
at 126, 126, and 126 Å (x, y, and z) to include all the amino acid
of GSK function. Increased expression of GSK 3 was reported in
residues which are present in rigid macromolecules. Auto Grid 4.2
the skeletal muscle of T2DM patients evidencing its role in insulin
Program, supplied with Auto Dock 4.2 was used to produce grid
signaling (Nikoulina et al., 2000).
maps. The spacing between grid points was 0.375 angstroms.
Several synthetic GSK-3 inhibitors have been
Auto Dock offers a variety of search algorithms
established to date. Very few studies have been conducted on
to explore a given docking problem. In the present study,
plant-derived compounds with pharmacoinformatics elucidation
Lamarckian Genetic Algorithm (LGA) was chosen search for the
for the identification of novel therapeutics for diabetes (Ahmed
best conformers. During the docking process, a maximum of 10
et al., 2014). However, the clinical trials are limited due to
conformers was considered. The population size was set to 150 and
their cytotoxicity, low pharmacokinetic and pharmacodynamic
the individuals were initialized randomly. The maximum number
characteristics. Hence, the development of effective GSK-3
inhibitors preferably from plant sources having a discrete of energy evaluation was set to 500000, the maximum number
mechanism of action on its substrates and the structure-based of generations 1000, the maximum number of a top individual
studies have provided the vital clues on the interactions shown that automatically survived set to 1, the mutation rate of 0.02,
by selective and non-selective ATP-competitive GSK-3 inhibitors the crossover rate of 0.8, Step sizes were 0.2 Å for translations,
(Wauwe et al., 2003). Recently, we have reported the computer- 5.0° for quaternions and 5.0° for torsions. Cluster tolerance 0.5 Å,
aided approach on aldose reductase inhibitory potential of external grid energy 1000.0, max initial energy 0.0, max number
gymnemic acid, trigonelline and ferulic acid (Roshana Devi and of retries 10000 and 10 LGA runs were performed.
Subramanian, 2017). Auto Dock results were analyzed to study the interactions
Plant-derived secondary metabolites have a wide array and the binding energy of the docked structure. It was run several
of therapeutic efficacy (Atanasov et al., 2015; Ota and Ulrih, times to get various docked conformations and to analyze predicted
2017; Liu et al., 2017). Gymnemic acid, a sweet taste suppressing docking energy. The best ligand-receptor structure from the docked
glycoside, is the major phytoingredient isolated from the leaves structures was chosen based on the lowest energy and minimal
of Gymnema Sylvestre. Trigonelline, a pyridine alkaloid, isolated solvent accessibility of the ligand. The docking results were
from the seeds of fenugreek (Trigonella foenum-graecum) and visualized using the Accelrys Visualizer discovery studio tool.
known for its hypoglycemic and hypolipidemic properties. Ferulic
acid, isolated from the oleo gum resin of Ferula asafetida has RESULTS AND DISCUSSION
received great attention in oriental research due to its significant In silico molecular docking is a method with predicts the
antioxidant properties. preferred orientation of a molecule to a second when they allowed
The present study involves the computer-aided for binding to each other to form a stable compound (Lengauer
molecular docking approach on the inhibition of GSK-3α and and Rarey, 1996). However, the knowledge of the preferential
GSK-3β activity by the above phytoingredients. orientation is essential to predict the strength of association or the
affinity binding between the two molecules based on their scoring
MATERIALS AND METHODS function.
Essentially, the molecular docking is a tricky process
Ligand preparation comprising of two parts namely the prediction and orientation of
The phytochemicals such as Gymnemic acid, the ligand and the affinity towards its target (Bissantz et al., 2000).
Trigonelline, and Ferulic acid were considered as ligand molecules. The relative orientation of the two interacting molecules such as
The phytochemicals were constructed using Chemsketch and then proteins, nucleic acids, carbohydrates, and lipids play a major role
converted into PDB file format by adding the hydrogen bonds. in signal transduction which in turn found useful for predicting the
strength and the type of signal generated. Thus, the lowest binding
Preparation of receptor protein
energy observed during the molecular docking plays an important
Crystal structure of glycogen synthase kinase-3 was role in rational drug designing (Kitchen et al., 2004).
retrieved from RCSB PDB. Preparation of glycogen synthase The identification and elucidation of GSK-3 in the
kinase-3 with the Auto Dock Tools involves the addition of regulation of various metabolic pathways result in the search
hydrogen atoms to the target enzyme for the preparation of protein for suitable GSK inhibitors as candidates for the prevention and
docking simulation.
152 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160

treatment of several chronic diseases (Mohammad et al., 2008). inhibitors preferably from plant origin with improved efficacy and
So far, a variety of molecules have been synthesized to inhibit the safety continues for the development of antidiabetic drugs. The
glycogen synthase kinase activity. However, none is found to be molecular structures of the phytoligands used in the present study
ideal due to several drawbacks. Hence, the search for novel GSK were presented in Figure 1.

Fig. 1: Molecular structures of phytoligands.

Fig. 2: Docking conformation of Gymnemic acid with Glycogen synthase kinase 3α using Auto Dock.

MOLECULAR DOCKING STUDIES OF GYMNEMIC kinase-3α and gymnemic acid was visualized as Figure 3.
ACID, TRIGONELLINE AND FERULIC ACID ON Table 1 represents the docking energy and the bonding distance
GLYCOGEN SYNTHASE KINASE 3 (Α & Β) between gymnemic acid and glycogen synthase kinase 3α. This
study shows that the gymnemic acid with glycogen synthase
Inhibition of Glycogen synthase kinase 3 activity by kinase 3α complex is stabilized by the hydrogen bonds of bond
Gymnemic acid length 2.43, 2.98, 1.87, 3.14, 2.61, and 3.05 Å with the residues
Figure 2 exemplifies the docking conformation TYR123, TYR123, TYR123, VAL108 ARG110, and ARG110
of gymnemic acid with glycogen synthase kinase 3α. The of GSK 3α, respectively. The interactions that play a significant
interactions of hydrogen bonds between glycogen synthase role in the determination of binding energy and stability of these
receptor-ligand complexes were recognized as hydrogen bonds.
 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160 153

The binding energy of the lowest energy conformer of gymnemic computationally and found to be −5.33 Kcal/mol.
acid with glycogen synthase kinase 3α complex was calculated

Fig. 3: Hydrogen bonds interaction between GSK3α and gymnemic acid using Accelrys Discovery Studio Visualizer.

Fig. 4: Docking conformation of Gymnemic acid with Glycogen synthase kinase 3β using Auto Dock.

Figure 4 illustrates the docking conformation hydrogen bonds of distance was 2.68, 3.16, 2.85, 2.80, 2.76, and
of gymnemic acid with glycogen synthase kinase 3β. The 3.05 Å. The docking energy for gymnemic acid with Glycogen
interactions of hydrogen bonds between glycogen synthase kinase synthase kinase 3β was found to be –4.69 Kcal/Mol.
and gymnemic acid was visualized as Figure 5. Table 2 shows
the docking energy and the bonding distance between gymnemic Inhibition of Glycogen synthase kinase 3 activity by
acid and glycogen synthase kinase 3β. The amino acids present Trigonelline
in the active site of glycogen synthase kinase 3β interacts with Docking conformation of Trigonelline with glycogen
gymnemic acid are found to be ARG148, ARG148 ARG148, synthase kinase 3α was depicted as Figure 6. The interactions
ARG144, and ARG144. The docking complex is stabilized by the of hydrogen bonds between glycogen synthase kinase 3α and
154 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160

Trigonelline were visualized in Figure 7. Table 3 represents glycogen synthase kinase 3β. The amino acids present in the active
the docking energy and the bonding distance for Trigonelline site of glycogen synthase kinase 3β interacts with Trigonelline are
with glycogen synthase kinase 3α. The amino acids present found to be ARG180, ARG180, ARG180, LYS205, and ARG96.
in the active site of glycogen synthase kinase 3α interacts with The docking Trigonelline with glycogen synthase kinase 3β
Trigonelline are found to be ARG62, ARG62, LYS147, VAL180, complex was stabilized by hydrogen bonds interaction and the
ARG146, ARG146, and ARG146 and the hydrogen bonding bonding distance was found to be 3.19, 3.16, 2.82, 2.80, and 2.99
distance between trigonelline and GSK 3α were found to be 2.87, Å. The binding energy for Trigonelline with Glycogen synthase
2.95, 2.83, 3.05, 2.92, 3.18, and 2.84 Å. The docking energy for kinase 3β was found to be –5.51 Kcal/Mol.
Trigonelline with Glycogen synthase kinase 3α was calculated
Table 4: Docking energy for trigonelline with Glycogen synthase kinase 3β.
computationally and found to be – 6.85 Kcal/Mol.
GSK3β Docking Energy
Table 1: Docking energy for Gymnemic acid with Glycogen synthase kinase 3α. Trigonelline Distance (Ǻ)
(Kcal/Mol)
Residue Atom
GSK3α Docking Energy
Gymnemic Acid Distance (Ǻ) ARG180 NH1 O 3.19
Residue Atom (Kcal/Mol)
ARG180 NH2 O 3.16
TYR123 OH O 2.43
ARG180 NH2 O 2.82 –5.51
TYR123 OH O 2.98
LYS205 NZ O 2.80
TYR123 OH H 1.87
–5.33
VAL108 N O 3.14 ARG96 NH1 O 2.99

ARG110 NE O 2.61
Table 5: Docking energy for ferulic acid with Glycogen synthase kinase 3α.
ARG110 NH2 O 3.05
GSK3α Docking Energy
Ferulic Acid Distance (Ǻ)
Residue Atom (Kcal/Mol)
Table 2: Docking energy for Gymnemic acid with Glycogen synthase kinase 3β.
SER169 OH H 2.07
GSK3β Docking Energy
Gymnemic Acid Distance (Ǻ)
Residue Atom (Kcal/Mol) SER169 OH H 3.02

ARG148 NH1 O 2.68 ARG146 NH2 O 3.04

VAL180 N O 2.95 –7.0

ARG148 NH2 O 3.16

ARG148 NH2 O 2.85 –4.69 LYS171 NZ O 3.03

ARG144 NH2 O 2.80 LYS171 NZ O 3.00

ARG144 NE O 2.76 ARG62 NH2 O 2.98

Table 3: Docking energy for trigonelline with Glycogen synthase kinase 3α. Inhibition of Glycogen synthase kinase 3 activity by Ferulic
acid
GSK3α Docking Energy
Trigonelline Distance (Ǻ)
(Kcal/Mol)
Figure 10 exemplifies the docking conformation of
Residue Atom ferulic acid with glycogen synthase kinase 3α. The interactions of
ARG62 NH1 O 2.87 hydrogen bonds between glycogen synthase kinase 3α and ferulic
acid were visualized using Accelrys discovery studio visualizer
ARG62 NH2 O 2.95 (Figure 11). Table 5 represents the docking energy and the
bonding distance for ferulic acid with glycogen synthase kinase
LYS147 NZ O 2.83
3α. The amino acids present in the active site of glycogen synthase
VAL180 N O 3.05 kinase 3α interacts with ferulic acid are found to be SER169,
–6.85
SER169, ARG146, VAL180, LYS171, LYS171, and ARG62.
ARG146 NH2 O 2.92 GSK 3α and ferulic acid were stabilized by the hydrogen bonds.
The bonding distance between ferulic acid with glycogen synthase
ARG146 NH2 O 3.18 kinase 3α was found to be 2.07, 3.02, 3.04, 2.95, 3.03, 3.00,
and 2.98 Å. The docking energy for ferulic acid with Glycogen
ARG146 NH1 O 2.84 synthase kinase 3α was found to be –7.0 Kcal/Mol.
Figure 12 illustrates the docking conformation of
The docking conformation of Trigonelline with ferulic acid with glycogen synthase kinase 3β. The interactions
glycogen synthase kinase 3β is illustrated in Figure 8. The of hydrogen bonds between glycogen synthase kinase and ferulic
interactions of hydrogen bonds between glycogen synthase kinase acid were visualized as Figure 13. Table 6 represents the docking
and Trigonelline were visualized as Figure 9. Table 4 represents energy and the bonding distance for ferulic acid with glycogen
the docking energy and the bonding distance for Trigonelline with synthase kinase 3β. Trigonelline with glycogen synthase kinase 3β
 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160 155

complex is stabilized by the hydrogen bonds of bond length 2.56, of GSK 3β, respectively. The binding energy for ferulic acid with
2.78 and 1.84 Å with the residues TYR127, TYR127, and SER66 Glycogen synthase kinase 3β was found to be –5.05 Kcal/Mol.

Fig. 5: Hydrogen bonds interaction between GSK3β and Gymnemic acid using Accelrys Discovery Studio Visualizer.

Fig. 6: Docking conformation of trigonelline with Glycogen synthase kinase 3α using Auto Dock.
156 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160

Fig. 7: Hydrogen bonds interaction between GSK3α and trigonelline using Accelrys Discovery Studio Visualizer.

Fig. 8: Docking conformation of trigonelline with Glycogen synthase kinase 3β using Auto Dock.

Table 6: Docking energy for ferulic acid with Glycogen synthase kinase 3β. energies of Gymnemic acid, Trigonelline and Ferulic acid with
Glycogen synthase kinase 3α and 3β were shown in Table 9.
GSK3β
Ferulic Acid Distance (Ǻ)
Docking The parameters analyzed in the present study include
Energy (Kcal/Mol)
Residue Atom hydrogen bond interactions, п–п interactions, binding energy,
TYR127 N O 2.56 active site residues and orientation of the phytochemicals with the
–5.05
receptors. These are considered as important indices of molecular
TYR127 N O 2.78
docking (Madeswaran et al., 2011). If a compound shows lesser
SER66 O H 1.84
binding energy, it implies that the compounds have higher activity.
The overall binding energies between phytoligands and The extent of forces of attraction or repulsion between the ligand
GSK-3α and 3β were depicted in Table 7. Table 8 depicts the and the receptor depends on the binding or intermolecular energy
inhibition constant of Gymnemic acid, Trigonelline and Ferulic (Madeswaran et al., 2012). Accordingly, the results of the present
acid with Glycogen synthase kinase 3α and 3β. Intermolecular study confirmed that the decrease in the binding energy, as well as
 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160 157

inhibition constant for the three bioactive compounds (ligands), acid on the activity of GSK was proved using molecular docking
is responsible for their GSK inhibitory activity. In conclusion, simulation.
the inhibitory role of the gymnemic acid, trigonelline, and ferulic

Fig. 9: Hydrogen bonds interaction between GSK3β and trigonelline using Accelrys Discovery Studio Visualizer.

Fig. 10: Docking conformation of ferulic acid with Glycogen synthase kinase 3α using Auto Dock.

Middha et al. (2013) reported that the binding activity of GSK-3β. In 2013, Shen and Lu reported that the citrus
interactions exhibited by the compounds of Hippophae inhibit the flavonoids inhibit the GSK-3β activity. Quinazoline derivatives
158 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160

inhibit the activity of GSK-3 and can be utilized for designing binding pockets and it may be due to the presence of chemical
of novel GSK-3β inhibitors (Sangu et al., 2014). Our findings structure and −OH functional groups present in the bioactive
were in accordance with the reported results. Gymnemic acid, compounds, which might be responsible for the inhibitory activity
Trigonelline, and Ferulic acid possess potential GSK inhibitory of GSK-3.

Fig. 11: Hydrogen bonds interactions between GSK3α and ferulic acid using Accelrys Discovery Studio Visualizer.

Fig. 12: Docking conformation of ferulic acid with Glycogen synthase kinase 3β using Auto Dock.

CONCLUSION highest binding energy and affinity to bind the molecular markers.
Structure-based drug design tool is an effective route of The molecular docking studies of the phytoligands with glycogen
drug discovery. From this, an idea to get the alternative for the synthase kinase showed the excellent inhibitory potential. In
existing drugs which have adverse effect after a prolonged period. conclusion, Gymnemic acid, Trigonelline, and Ferulic acid have
Natural inhibitory compounds have no adverse effects with the potential to maintain normoglycemia via the inhibition of
 Devi et al. / Journal of Applied Pharmaceutical Science 8 (04); 2018: 150-160 159

GSK-3 activity. This study might be valuable for the development into the therapeutics for diabetes mellitus.
of active pharmacophore discovery and offering novel insights

Fig. 13: Hydrogen bonds interaction between GSK3β and ferulic acid using Accelrys Discovery Studio Visualizer.

Table 7: The overall docking energy for Gymnemic acid, Trigonelline and CONFLICT OF INTEREST
Ferulic acid with Glycogen synthase kinase 3α and 3β.
The authors declare that there is no conflict of interest.
Docking Energy (Kcal/Mol)
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