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International Journal of Pharma and Bio Sciences

RESEARCH ARTICLE BIOINFORMATICS


ARTICALTICLE

MOLECULAR DOCKING STUDIES OF 1, 2 DISUBSTITUTED IDOPYRANOSE


FROM VITEX NEGUNDO WITH ANTI-DIABETIC ACTIVITY OF TYPE 2 DIABETES

Corresponding Author

PAPPU SRINIVASAN
1
Department of Bioinformatics, Alagappa University, Karaikudi –
630 003, India

Co Authors

1
ARUMUGAM SUDHA, 2RAMAR MANIKANDAN AND
3
CHINNASAMY ARULVASU
2
Department of Animal Health & Management, Alagappa University, Karaikudi – 630 003, India
3
Department of Zoology, University of Madras, Chennai – 600 025

ABSTRACT

Type 2 diabetes is one of the major life threatening diseases worldwide these cases are
progressing at an incremental rate every year and number of research works are going on to
control the disease by targeting its enzymes or proteins. The medicinal properties of Vitex negundo
and one of its compounds, 1, 2 disubstituted idopyranose (C23H28O12) was checked against
diabetes mellitus by molecular docking with various proteins which are involved in the carbohydrate
metabolism. The inhibitor, 1, 2 disubstituted idopyranose was found to be increased insulin
sensitivity and normalize blood glucose level by binding in the active sites of the protein and thus
useful therapeutic agent for the herbal therapy of diabetes. The docking method to explore the
ability of 1, 2 disubstituted idopyranose bound to the active binding site in the proteins and showed
that the inhibitor is the best binder of the present study. We concluded that the natural products with
interesting biological properties and structural diversity have often served as valuable lead drug
candidates for the treatment of human diseases and also it replaces the chemically synthesized
drugs which cause side effects.

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KEYWORDS

Diabetes mellitus, Vitex negundo, 1, 2 disubstituted idopyranose, Docking, Glide

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a genetically two forms, i.e., as a soluble homo-dimer and
heterogeneous, polygenic disease with a as a type II integral plasma membrane
complex inheritance pattern and is caused by glycoprotein which is abundantly expressed on
genetic predisposition and environmental factors a variety of cell surfaces (Bjelke et al., 2004;
(LeRoith, 2002). The disease is characterized by Abbott and Gorrell, 2002; Lambeir et al., 1997;
altered expression of many genes and their Duke-Cohan et al., 1996). DPP-IV deactivates
products in several tissue types (Gerich, 1998; the incretin hormones GLP-1 and GIP by
Gloyn, 2003). Number of proteins was cleaving the penultimate proline or alanine
considered as a target to control the diabetes from the N-terminal (P1-position) of the
mellitus. In the present study, four proteins such peptide, since the intact N-terminal ends of
as human maltase-glucoamylase (MGA), both GLP-1 and GIP are essential for biological
dipeptidyl peptidase-4 (DPP-4), aldose activity (Adelhorst et al., 1994; Rolin et al.,
reductase (AR) and glycogen synthase kinase-3 2004). The cleavage of the N-terminal
(GSK-3) are considered as targets for the dipeptide segment by DPP-IV plays an
inhibitor, 1, 2 disubstituted idopyranose (C23- important role in maintaining glucose
H28O12), derived from the leaves of the medicinal homeostasis. Thus, shielding incretin
plant, Vitex negundo Linn (Verbanaceae). MGA hormones from catastrophic effects of DPP-IV
is an enzyme responsible for catalyzing the last enzyme by the administration of inhibitors will
glucose releasing step in starch digestion. MGA maintain the concentrations of incretin
accounts for all glucoamylase activity, 20% of hormones and prolong their proficient
the maltase activity and 1% of the sucrase antidiabetic action. Aldose reductase (AR) is
activity (Semenza et al., 1989). Human MGA the first enzyme of the polyol pathway and is
encoded by the gene MGAM (Buford et al., widely distributed in mammalian tissues. Due
2003; Roy et al., 2002) is an alpha glucosidase to increased aldose reductase activity, the
responsible for hydrolysis of α-1, 4- linkages accumulation of intracellular sorbitol is also
from the non-reducing end of the maltose raised. It implicates the development of various
oligosaccharides (Nichols et al., 1998) and secondary complications of diabetes mellitus
belongs to glycoside hydrolase family 31. It is (Muthenna et al., 2009). Glycogen synthase
type II membrane protein, 1857 amino acids in kinase-3 (GSK-3) is a unique multifunctional
length anchored in the brush border epithelial serine/threonine kinase and it was inactivated
cells of the small intestine. Dipeptidyl peptidase- by phosphorylation. In response to insulin
IV (DPP-IV) is a multifunctional protein involved binding, PKB/AKT phosphorylates GSK-3 on
in many physiological processes such as binding serine 9, which prevents the enzyme from
protein, receptor and proteolytic enzyme. DPP- phosphorylating glycogen synthase (Frame et
IV was discovered in the late 80’s, as a serine al., 2001; Mukai et al., 2002; Doble and
peptidase belonging to the S9b protein family Woodgett, 2003). Unphosphorylated glycogen
(Ogata et al., 1989). This ecto-enzyme exists in synthase is active and able to synthesize

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glycogen. Thus it plays a key role in the involves variety of methods to identify novel
transduction of regulatory and proliferative compounds. One such method is the docking
signals arising out at the cell membrane in the of the drug molecule with the receptor (target).
insulin signalling pathway, leading to potential The site of drug action, which is ultimately
modulation of blood glucose levels (McManus et responsible for the pharmaceutical effect, is a
al., 2005). GSK-3 is also unique and it requires a receptor and docking is the process by which
substrate that has been phosphorylated by a two molecules fit together in 3D space. A
distinct kinase before it can phosphorylate the bioactive compound 1, 2 disubstituted
substrate. idopyranose (Fig.1) has been already reported
Computational Biology and bioinformatics have by us from the leaves of medicinal plant, Vitex
the potential not only of speeding up the drug negundo Linn (Verbanaceae) and this
discovery process thus reducing the costs, but compound helps in regeneration of damaged
also of changing the way drugs are designed. pancreatic ß-cells and hyperglycaemic nature
Rational drug design (RDD) helps to facilitate against streptozotocin-induced diabetes in in
and speedup the drug designing process, which vitro studies (Manikandan et al., 2009).

Figure 1
1, 2 disubstituted idopyranose

The aim of the present study is to investigate the


inhibitory activity of the compound, 1, 2 Computational methods with Glide Version
disubstituted idopyranose on type 2 diabetes by 5.5
molecular docking studies and to analyze the All computational studies were carried out
ADME/T properties of the compound for drug like using Glide version 5.5, installed in a single
candidates by using the Schrodinger software machine running on Intel CoreTM 2 Duo
9.0 and hence it would serve as to design drug processor with 1GB RAM and 160 GB hard
alternative to diabetes. disk with Red Hat Linux Enterprise version 5.0
as the operating system.
MATERIALS AND METHODS
Ligand preparation
Docking studies were performed for 1, 2 The structure of the compound, 1, 2
disubstituted idopyranose (C23H28O12) with target disubstituted idopyranose (C23H28O12) was
proteins by Glide 5.5 module of Schrodinger drawn by using ChemSketch (ACDLABS 12.0)
suite. and converted to 3D structure with the help of
3D optimization tool. By using the LigPrep (2.3)

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module (Ligprep, Version 2.3, 2009), the drawn the scoring function resembles an experimental
ligand was geometry optimized by using the binding mode as determined by X-ray
Optimized Potentials for Liquid Simulations-2005 crystallography. In the present study, the
(OPLS-2005) force field with the Steepest docking of proteins with their already presented
Descent followed by truncated Newton ligand was performed to test the reliability and
Conjugate gradient protocol. Partial atomic reproducibility of the docking protocol for our
charges were computed using the OPLS-2005 study. The root mean square deviations
force field. The LigPrep is a utility in Schrodinger (RMSD) between the predicted conformation
software suite that combines tools for generating and the observed X-ray crystallographic
3D structures from 1D (Smiles) and 2D (SDF) conformation of the ligand by Glide (3 Å) was
representation, searching for tautomers and analyzed. This indicates the reliability of the
steric isomers and geometry minimization of docking method in reproducing the
ligands. Finally, 32 poses had been prepared experimentally observed binding mode for
with different tautomeric and steric features for target proteins.
docking studies.
Docking studies
Protein preparation The docking studies were done for all the
The X-ray crystal structures of all the proteins prepared proteins separately. Docking studies
viz., maltase glucoamylase (MGA), dipeptidyl on compounds prepared through LigPrep were
peptidase-4 (DPP-4), aldose reductase and carried out in the active site of the protein.
glycogen synthase kinase-3 (GSK-3) were Receptor Vander Waals scaling for the non
obtained from the RCSB protein data bank polar atoms was set to 0.9 which makes the
(http://www.rcsb.org/pdb). After evaluating protein site “roomier” by moving back the
numbers of entries, the best proteins were surface of non Polar Regions of the protein and
selected by analyzing the protein with ligand. This kind of adjustments emulate to
Ramachandran plot and ProCheck using SAVS some extent the effect of breathing motion to
server based on ligand and number of the protein site, it is a kind of giving breathing
disallowed regions (Laskowaski et al., 1993; to the receptor, this approach softens the
Morris and MacArthur, 1992; Ramachandran et active site region of the receptor making it
al., 1963). After selection, Protein preparation flexible (Taverna and Goldstein, 2002). The
wizard of Schrodinger suite has been used to prepared protein and the ligand were employed
prepare protein. The proteins were preprocessed to build energy grids using the default value of
separately by deleting the substrate cofactor as protein atom scaling (1.0 Å) within a cubic box,
well as the crystallographically observed water centered around the centroid of the X-ray
molecules (water without H bonds), correcting ligand pose. After Grid generation, the ligand
the mistakes in PDB file, optimizing hydrogen was docked with the protein by using Glide 5.5
bonds. After assigning charge and protonation module (Glide, Version 5.5, 2009) in extra
state finally energy minimization with root mean precision mode (XP) which uses MCSA (Monte
square deviation (RMSD) value of 0.30Å was Carlo Based Simulated Algorithm) based
done using OPLS2005 force field. minimization. The best docked pose (with
lowest Glide Score value) obtained from Glide
Validation of the docking protocol in Glide (Hamilton-Miller, 1995; Friesner et al., 2004;
The most suitable method of evaluating the Friesner et al., 2006; Halgren et al., 2004) was
accuracy of a docking procedure is to determine analysed. The binding energy was calculated
how closely the lowest energy pose predicted by by Liaison module (Liaison, Version 5.5, 2009).

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RESULTS AND DISCUSSION
ADME/T property analysis
The above prepared ligands were then The docking simulation technique was
neutralized and checked for their ADME/T performed using Glide module (Schrodinger
properties using QikProp 2.3 module (QikProp, suite) with plant-derived compound 1, 2
Version 3.2, 2009). QikProp helps in analyzing disubstituted idopyranose and it was docked
the pharmacokinetics and pharmacodynamics of into each of four different targets. 2qmj for
the ligand by accessing the drug like properties. maltase glucoamylase (Fig. 2), 3f8s for
Predicted significant ADME/T properties such as dipeptidyl peptidase-4 (Fig. 3), 3f7z for
Molecular weight (MW), permeability through glycogen synthase kinase-3 (Fig. 4) and 3g5e
MDCK Cells (QPlogMDCK), Qik Prop predicted for aldose reductase (Fig. 5) were selected
log IC50 value for blockage of K+ channels after evaluating number of geometries from
(QPlogHERG), QikProp predicted gut-blood protein data bank (PDB) for docking studies.
barrier (QPPCaco) and violations of the For validating the software, the proteins were
Lipinski’s rule of five (LROF) are reported here . redocked with the already bound ligand.

Figure 2 Figure 3
Maltase Glucoamylase (2qmj) Dipeptidyl peptidase-4 (3f8s)

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Figure 4 Figure 5
Glycogen synthase kinase-3(3f7z) Aldose Reductase (3g5e)

By docking the known ligand acarbose with four target proteins, maltase glucoamylase
maltase glucoamylase (Sim et al., 2008), PF2 (PDB ID: 2qmj), dipeptidyl peptidase-4 (PDB
with dipeptidyl peptidase-4 (Ammirati et al., ID: 3f8s), aldose reductase (PDB ID: 3g5e) and
2009), IDD740 with aldose reductase (Van et al., glycogen synthase kinase-3 (PDB ID: 3f7z)
2009) and oxadiozole with GSK-3 (Saitoh, M., separately. In that 32 poses, the best 10 poses
2009), RMSD were checked for the reliability of (1 to 10) were selected according to the Glide
docking method in reproducing the XP score and lowest energy docked
experimentally observed binding mode of the conformation and subjected to the energy
proteins. The ligand, 1, 2 disubstituted minimization using Liasion module. Table 1
idopyranose (C23H28O12) prepared with 32 poses summarizes the result of the docking study
using LigPrep (Fig. 2 6, 7) were docked with presented as Glide score and Glide energies.

Figure 6
1, 2 disubstituted idopyranose- 32 poses

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Figure 7 (1-12)
1, 2 disubstituted idopyranose with 32 Poses

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Figure 7 (13-24)
1, 2 disubstituted idopyranose with 32 Poses

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Figure 7 (25-32)
1, 2 disubstituted idopyranose with 32 Poses

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Table 1
Docking result of the ligand, 1, 2 disubstituted idopyranose with 32 Poses

Ligand 2qmj 3f8s 3g5e 3f7z


Poses
Glide Glide Glide Glide Glide Glide Glide Glide
Score Energy Score Energy Score Energy Score Energy
(XP) (kcal/mol) (XP) (kcal/mol) (XP) (kcal/mol) (XP) (kcal/mol)
1. -8.19 -40.40 -10.06 -49.44 -6.78 -40.04 -10.26 -48.86
*2. -7.35 -47.02 -9.86 -52.25 -6.65 -40.11 -9.41 -41.16
*3. -6.42 -47.53 -8.76 -52.41 -6.51 -39.36 -9.56 -51.00
4. -6.41 -47.25 -8.76 -52.08 -6.26 -38.67 -9.50 -52.81
5. -6.40 -43.11 -8.53 -48.87 -6.21 -40.97 -9.27 -39.79
6. -6.34 -44.27 -8.22 -45.77 -5.99 -43.16 -9.22 -52.95
7. -6.31 -44.76 -8.09 -47.19 -5.83 -38.62 -9.16 -49.72
8. -6.23 -43.07 -8.07 -50.26 -5.77 -38.04 -9.04 -51.22
9. -6.17 -33.50 -7.95 -50.55 -5.76 -42.30 -8.90 -54.53
10 -6.01 -47.21 -7.94 -50.14 -5.63 -37.04 -8.89 -47.75
11 -5.99 -43.25 -7.94 -47.27 -5.60 -33.41 -8.76 -44.62
12. -5.90 -41.33 -7.92 -50.70 -5.53 -38.00 -8.72 -48.40
13. -5.87 -40.19 -7.83 -47.20 -5.45 -39.82 -8.71 -53.48
14. -5.87 -47.73 -7.82 -52.02 -5.42 -43.79 -8.67 -46.66
15. -5.87 -42.05 -7.75 -42.59 -5.21 -35.75 -8.38 -46.48
16. -5.86 -44.46 -7.72 -53.03 -5.18 -37.62 -8.19 -48.74
17. -5.77 -43.74 -7.58 -42.36 -5.12 -37.03 -8.11 -46.84
18. -5.68 -37.29 -7.55 -46.38 -5.05 -31.68 -8.10 -46.36
19. -5.59 -45.92 -7.50 -46.44 -5.04 -37.89 -8.09 -43.08
20. -5.57 -38.37 -7.38 -49.24 -4.98 -39.10 -8.07 -48.70
21. -5.37 -43.31 -7.37 -46.03 -4.97 -32.95 -7.97 -49.62
22. -5.37 -41.20 -7.22 -48.40 -4.95 -37.34 -7.89 -47.73
23. -5.33 -39.98 -7.19 -49.96 -4.92 -35.64 -7.80 -42.88
24. -5.32 -39.14 -7.06 -49.44 -4.81 -37.47 -7.66 -52.88
25. -5.31 -41.33 -6.94 -39.09 -4.79 -37.14 -7.65 -44.84
26. -5.03 -35.53 -6.84 -46.95 -4.46 -42.87 -7.63 -50.65
27. -5.03 -45.48 -6.82 -50.24 -4.43 -38.66 -7.61 -46.76
28. -4.89 -42.23 -6.63 -45.19 -4.38 -38.80 -7.58 -43.77
29. -4.81 -44.49 -6.37 -46.39 -4.36 -38.83 -7.41 -48.49
30. -4.75 -44.72 -6.26 -43.90 -4.23 -35.80 -7.30 -49.76
31. -4.48 -36.71 -6.21 -42.03 -4.17 -37.17 -7.02 -48.97
32. -3.87 -36.76 -6.06 -46.30 -3.92 -42.59 -6.93 -41.15

* Ligand pose showing high glide score and low bound energy

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According to the docking result, the ligand was 3f7z (Glide Score, -9.56 and Glide Energy, -
selected with best dock score and low bound 51.00 kcal/mol) (Fig. 10).The docking
energy. In that, the ligand pose 2 had the good interactions between the selected natural
glide score and energy compared to other poses compound and the known inhibitor of each
for 2qmj (Glide Score, -7.35 and Glide Energy, - target were compared and from the result it
47.02 kcal/mol) (Fig. 8), 3f8s (Glide Score, -9.86 was revealed that the idopyranose possess
and Glide Energy, -52.25 kcal/mol) (Fig. 9), and better score for 3f8s and 3f7z than the
3g5e (Glide Score, -6.65 and Glide Energy, - previously bound one (Table. 2).
40.11 kcal/mol) (Fig. 11) and ligand pose 3 for

Figure 8 Figure 9
1, 2 disubstituted idopyranose 1, 2 disubstituted idopyranose
bound with 2qmj bound with 3f8s

Figure 10 Figure 11
1, 2 disubstituted idopyranose 1, 2 disubstituted idopyranose
bound with 3f7z bound with 3g5e

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Table 2
Comparison of best ligand score between 1, 2 disubstituted idopyranose and known
inhibitors
Pdb Idopyranose Known Inhibitors
Id Glide Glide No of Hydrogen bond Glide Glide No of
Score Energy interactions Score Energy Hydrogen
(XP) (kcal/mol) (XP) (kcal/mol) bond
interactions
2qmj -7.35 -47.02 3 -10.99 -57.72 6

3f8s -9.86 -52.25 6 -5.96 -42.83 2

3g5e -6.65 -40.11 5 -6.16 -75.02 6

3f7z -9.56 -51.00 5 -8.80 -55.94 3

The bioactive compound also interacted the (Gln185,Gln185,Arg 125,Arg141and Pro136)


proteins with more number of hydrogen bonds with GSK-3(3f7z), in their binding pocket. The
than known inhibitors, six hydrogen bond Liasion values (-80.34 kcal/mol for DPP-4 and -
interactions (Arg125, Asn710, Arg125, Glu205, 99.47 kcal/mol for GSK-3) also confirmed the
Glu205 and Glu206) with the protein DPP- result with good binding energy (Table. 3).
4(3f8s), five hydrogen bond interactions
Table 3
Liaison binding energy for protein-ligand complex
Ligand Liaison Values
Poses 2qmj 3f8s 3g5e 3f7z
1 -18.51 -71.06 -76.67 -55.16

2* -13.05 -80.34 -56.55 -99.47

3 -14.58 -70.61 -42.59 -55.32

4 -9.98 -62.91 -94.47 -77.12


5 -9.62 -84.33 -68.83 -75.58
6 -33.24 -66.36 -65.44 -78.75
7 1.61 -86.73 -61.29 -58.83
8 -33.70 -26.73 -41.03 4.27
9 15.20 -71.13 -101.19 -47.90
10 11.45 -37.42 -72.60 -15.97
* Ligand pose with good liaison score

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Several reports revealed that the extract of the medicinal plant, Vitex negundo possessed anti-
diabetic properties (Irene et al., 2006). The anti-diabetic activity of 1, 2 disubstituted idopyranose had
been determined in Wistar rats (Manikandan et al., 2009). The ADME/T prediction of 1, 2
disubstituted idopyranose (C23H28O12) shows good result with least number of stars and least number
of violations (Table. 4). From this result, we can suggest that 1, 2 disubstituted idopyranose is a
potent inhibitor of dipeptidyl peptidase-4 and glycogen synthase kinase-3 than the commercially
available drugs.

Table 4
ADME/T properties of 1, 2 disubstituted idopyranose

Descriptors/Properties Value

Mol_MW 498.483
QPlogMDCK 1.921
QPlogHERG -3.135
LROF 2
QPPCaco 4.709
Stars 2
QPlogKp -5.288
QPlogS -2.779
QPlogBB -2.889
QPpolrz 42.933

CONCLUSION disubstituted idopyranose in the target protein’s


active site (dipeptidyl peptidase-4 and
glycogen synthase kinase-3) which resulted in
The Protein-Ligand interaction plays a significant
inhibition of enzyme activity. The binding
role in structural based drug designing. In the
energy of the ligand-protein interactions also
present work we have docked the ligand, 1, 2
confirmed that the ligand tightly fit to the
disubstituted idopyranose (C23H28O12) from the
macromolecule, protein. From the results
medicinal plant with the proteins that are used as
obtained, it will be essential to understand the
the target for Type 2 diabetes. The analysis of
important structural features required to
the docking result allowed us to know the
enhance the inhibitory activities and further it
efficiency of the natural bioactive compound to
will help to produce augmented inhibitory
control the diabetes. The docking study revealed
compounds.
the binding orientation of the natural ligand 1, 2

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