an investigation of antidiabetic activities

1 23

Medicinal Chemistry Research ISSN 1054-2523 Med Chem ResDOI 10.1007/s00044-013-0794-y

An investigation of antidiabetic activitiesof bioactive compounds in Euphorbiahirta Linn using molecular docking andpharmacophore

Quy Trinh & Ly Le

1 23

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ORIGINAL RESEARCH

An investigation of antidiabetic activities of bioactive compoundsin Euphorbia hirta Linn using molecular dockingand pharmacophore

Quy Trinh Ly Le

Received: 20 May 2013 / Accepted: 12 September 2013

Springer Science+Business Media New York 2013

Abstract Herbal remedies have been considered as

potential medication for diabetes type 2 treatment. Bitter

melons, onions, or Goryeong Ginsengs are popular herbals

and their functions in diabetes patients have been well

documented. Recently, the Euphorbia hirta has been

shown to have strong effects on diabetes in mice, however,

there has been no research clearly indicating what the

active compound is. The main purpose of the current study

was therefore to evaluate whether a relationship exists

between various bioactive compounds in E. hirta Linn and

targeted protein relating diabetes type 2 in human. In view

of this, extraction from E. hirta Linn was tested if they

contained the bioactive compounds. This process involved

the docking of 3D structures of those substances (ligand)

into targeted proteins: 11-b hydroxysteroid dehydrogenasetype 1, glutamine: fructose-6-phosphate amidotransferase,

protein phosphatase, and mono-ADP-ribosyltransferase

sirtuin-6. Then, LigandScout was applied to evaluate the

bond formed between ligand and the binding pocket in the

protein. These test identified in eight substances with high

binding affinity (\-8.0 kcal/mol) to all four interestedproteins of this article. The substances are quercetrin, rutin,

myricitrin, cyanidin 3,5-O-diglucoside, pelargonium 3,5-

diglucose in flavonoid family and a-amyrine, b-amyrine,

taraxerol in terpenes group. The result can be explained

by the 2D picture which showed hydrophobic interaction,

hydrogen bond acceptor, and hydrogen bond donor form-

ing between carbonyl oxygen molecules of ligand with free

residues in the protein. These pictures of the bonding

provide evidence that E. hirta Linn may prove to be an

effective treatment for diabetes type 2.

Keywords Diabetes type 2 Euphorbia hirta Linn Molecular docking Pharmacophore analysis

Introduction

Diabetes, one of the metabolic diseases that have high

blood sugar as a pathognomonic symptom, is spreading

like an epidemic. Worldwide, the number of patients

climbed steeply from 171 million in 2000 to 366 million in

2030 (Wild et al., 2004) and *90 % are of type 2 (Inter-national Diabetes Federation, 2006). A person with this

type of diabetes suffers a combination of insulin resistance

and a weakness in insulin production. Insulin resistance is

considered as stage one in diabetes type 2. In this phase, the

glucose, energy molecule of the cell cannot cross the cell

membrane due to blocking of the insulin receptor at the cell

surface. This result is a high glucose concentration in the

blood stream. To solve the problem, the pancreatic beta

cells produce extra insulin to maintain glucose in the nor-

mal range. However, this process is only effective in the

short term as burnout beta cell occurs. The failure for beta

cell to produce the extra insulin is the second stage of

diabetes type 2.

Determination of the best treatment for diabetes type 2

is complicated because this is a progressive disease. Cur-

rently, insulin combined with other drugs is the preferred

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00044-013-0794-y) contains supplementarymaterial, which is available to authorized users.

Q. Trinh L. LeSchool of Biotechnology, International UniversityVietnam

National University, Ho Chi Minh City, Vietnam

L. Le (&)Life Science Laboratory, Institute of Computational Science

and Technology, Ho Chi Minh City, Vietnam

e-mail: [email protected]

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Med Chem Res

DOI 10.1007/s00044-013-0794-y

MEDICINALCHEMISTRYRESEARCH

Author's personal copy

treatment method. Recently, natural herbal medicines are

preferable options. A study by Modak and coworkers have

provided a list of several medicinal plants used for diabetes

treatment (Modak et al., 2007). Several of them, such as

Caesalpinia bonducella (L) Roxb (Chandramohan et al.,

2008), Allium cepa (Onion) (G. B. Kavishankar et al.,

2011), Vitis vinifera and Euonymus alatus (Chan et al.,

2012), share a high concentration of Flavonoid compounds

including Quercetin, Kaemferol, Cyanidin, and Pelargo-

nium. Our study focuses on Euphorbia hirta, one member

of Euphorbiaceae family which has high concentration of

these bioactive compounds in their extraction. E. hirta has

been reported to be effective in reducing diabetes in mice

in vitro studies (Anup et al., 2012; Sunil and Rashmi,

2010). When, the ethanol extracted compound from the

leaves, stems, and flowers of E. hirta was applied to mice

which had induced diabetes by a single intraperitoneal

injection of streptozotocin (150 mg/kg), the result revealed

that compounds displayed antihyperglycemic activity in

the diabetic mice. To further understand this result, the

current study focuses on identifying the bioactivity of the

antidiabetes components of the ethanol extracts of E. hirta

by using them as ligand molecules for four targeted pro-

teins to determine which compound is an effective binder.

E. hirta contains three families of biomolecular com-

pounds such as tannin, flavonoid, and terpenes (Moham-

mad et al., 2010; Sandeep and Chandrakant, 2011). Tannin

and flavonoid are strong antioxidants (Pietta, 2000; Rield

and Hagerman, 2001). Quercitrin, one compound in Fla-

vonoid group, was good illustration. In the thiobarbituric

acid (TBA) experiment quercitrin showed strong antioxi-

dant activity, giving 92.5 % inhibition and the IC50 was

calculated to 23.40 lM (Basma et al., 2011). Products ofoxidation have been shown to play an essential role in the

pathogenesis of diabetes type 1 and 2 (Maritim et al.,

2003). In addition, the combination of high level of free

radicals and inactivation of antioxidant defense have been

shown to cause damage in cellular organelles and to the

production of insulin (Maritim et al., 2003). Therefore,

antioxidants such as tannin and flavonoid are considered to

have potential as therapeutic drugs for diabetes treatment.

Both flavonoid and terpenes from medicinal plants have

already been shown to have strong effects on diabetes

(Mankil et al., 2006). In light of this evidence, the current

study will screen a range of bioactive compounds from all

the three families to determine if and how they interact

with proteins important to human diabetes type 2.

Several proteins which were involved in glucose

metabolism consequently related to diabetes type 2. From

our intensive review on targeted proteins for antidiabetic

drug development (Trang and Ly, 2012), these important

target proteins including 11-b hydroxysteroid dehydroge-nase type 1 (11b-HSD1), Glutamine fructose-6-phosphate

amidotransferase (GFPT or GFAT), protein phosphatase

(PPM1B), and Mono-ADP-ribosyltransferase sirtuin-6

(SIRT6) were selected as receptors in this study.

Material and methodology

Molecular docking

Receptor

11-b HSD1, GFAT, PPM1B, and SIRT6 are the proteinsrelating to diabetes type 2 in humans (Hasan et al., 2002;

Trang and Ly, 2012; Vogel, 2002; Shi, 2009; Nerlich

et al., 1998). The 3D structures of these molecules taken

from Protein Data Bank are as follows: 11b-HSD1 (PDBcode 1XU7), GFAT (PDB code 2ZJ4), PPM1B (PDB

code 2P8E), and SIRT6 (PDB code 3K35). All these

structures were tested again at the binding site to verify the

capacity of the model in reproducing experimental obser-

vations with new ligand. In view of this, 11b-HSD1(PDB code 1XU7) was tested again with molecule:

NADPH dihydro-nicotinamide-adenine-dinucleotide phos-

phate; GFAT (PDB code 2ZJ4) was tested with 2-deoxy-2-

amino glucitol-6-phosphate; SIRT6 (PDB code 3K35) with

adenosine-5-diphosphoribose; and PPM1B (PDB code

2P8E) with cysteine sulfonic acid. They served as control

docking models illustrated in supplementary Table 4. This

work was done by Autodock vina in molecular docking

experiment and VMD in visualization (Humphrey et al.,

1996).

Bioactive compounds in E. hirta

Most of the 3D structures of drug molecules in E. hirta

were downloaded from PubChem Compound section of

National Center for Biotechnology Information (NCBI).

For molecules with unknown structure, the 3D models

were built based on 2D picture by GaussView 5.0, opti-

mized by Gaussian with Hatree-Fock method, and the

basis-set 6-31G* to increase reliability of structure. The 2D

structures of 27 ligands are illustrated in Table 1.

Docking simulations

The docking process was done using Autodock Vina (Oleg

and Arthur, 2009).

Autodocktool, one section in Molecular Graphic Labo-

ratory, was applied to build a complete pdbqt file name of

ligands and receptors. Receptor preparation was carried out

by four major sub-steps: (i) Adding polar hydrogen, (ii)

Removing water molecule, (iii) Computation of Gasteiger

charges, and (iv) Location of Grid box (supplementary

Med Chem Res

123


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Med Chem Res

123


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Med Chem Res

123


Fig. 7). The site of Grid Box is illustrated in Table 2. For

setting the ligands, the 3D structure in pdb file-type was

loaded into Autodocktool to detect the root and convert it

to pdbqt.

Before switching on the Autodock Vina, one configure

file was built to encode information for starting this pro-

gram. The content of configure file was determined as

position of receptor file, ligand file, data of Grid-boxs

three coordinates (Table 2), the size of Gridbox which was

set up in 30 9 30 9 30 points, number of modes which

were ten, and the energy range which was set up at 9 kcal/

mol.

Pharmacophore modeling

This part of process was carried out using the pharmaco-

phore tool included in LigandScout. The program showed

us the 2D and 3D structure with the position and interaction

of ligand in the binding pocket of the receptor. From these

2D pictures, some types of bond were identified by color

and symbol. Four features namely hydrogen bond acceptor

(HBA), hydrogen bond donor (HBD), negative ionizable

area, hydrophobic interaction were labeled as red arrow,

green arrow, red star, and orange bubble (supporting

information), respectively.

Result and discussion

Free energy binding of bioactive compound to targeted

protein related to diabetes type 2

In order to investigate the binding capacity of bioactive

compounds in E. hirta Linn on proteins related to diabetes

type 2 in humans, we docked the compounds to the pro-

teins. Results showed that the absolute value of binding

energy ranged from 7.0 to 12.8 kcal/mol (Fig. 2). The

group of terpenes including a-amyrine, b-amyrine, friede-lin, taraxerol, taraxerone, and cycloartenol showed the best

results. All receptor for terpenes group had particularlyTa

ble

1co

nti

nu

ed

Tar

axer

ol

Tar

axer

on

eF

ried

elin

Table 2 Position of the Grid box center in four protein molecules

Protein molecule PDB code X, Y, Z coordination (A)

X Y Z

11b-HSD1 1XU7 18.125 -27.72 -0.34

GFAT 2ZJ4 8.27 4.54 -7.67

PPM1B 2P8E -11.72 -18.53 9.86

SIRT6 3K35 14.5 -18.02 17.04

Med Chem Res

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high binding affinities with the highest at 11b-HSD1 (PDBcode 1XU7) which being 100 % larger than 11 (kcal/mol).

The next highest positions were SIRT6, GFAT, and

PPM1B (Fig. 1). For the terpenes group, the line for 11b-HSD1 stayed at the upper level when compared to the other

three receptors. For the ligands tested, terpenes were

therefore considered to be the best drug candidate for

diabetes type 2 and the three compounds that had[8 kcal/mol in terms of absolute value in binding affinity were

chosen for pharmacophore modeling. They were a-amy-rine, b-amyrine, and taraxerol. The high binding efficiencyis thought to be due to the multiple methyl groups in the

structure as these functional groups have a strong ability to

construct hydrophobic bonds with the free residue of the

receptor.

The flavonoid family had the largest number of ligands

and some of these also had high binding affinity to all four

receptors. Five of these quercitrin, rutin, myricitrin, cy-

anidin 3,5-O-diglucoside, pelargonium 3,5-diglucose were

selected for pharmacophore modeling step. Unsurprisingly,

the five molecules had multiple aromatic phenol rings in

their structure which is characteristic of polyphenol family.

This structure contains a high number of hydroxyl groups

which serve to facilitate ligands in forming hydrogen bonds

with free residue of receptor. In addition, to containing a

high number of ligands with high binding capacities, the

flavonoid family also contained three compounds (querci-

tol, rhamnose, and camphol) which had the lowest binding

affinity. The absolute value for these three ligands is shown

sequentially in Table 1. They all share a simple structure

with only one ring and few hydroxyl groups outside which

may explain their low binding affinity. Thus, these mole-

cules appear to have a low capacity to form a complex with

the four target proteins.

The tannin family also had molecules which bound well

to the receptors, but there was no representative molecule

for pharmacophore docking. However, they displayed

strong interaction with 11b-HSD1, GFAT1, SIRT6, and lowinteraction with PPM1B. Neuchlogenic acid and 3,4 dio

galloy-quinic acid are illustrated in supplementary Table 3.

From the results of this section, we determined that eight

compounds showed strong binding capacity (|binding

energy| [8.0 kcal/mol) to all four 11b-HSD1, SIRT6,GFAT, and PPM1B receptors. Three of them belong to

terpenes group (a-amyrine, b-amyrine, and taraxerol), theother five are members of flavonoid family (quercitrin,

rutin, myricitrin, cyanidin 3,5-O-diglucoside, and pelargo-

nium 3,5-diglucose). Five of them have structure of poly-

phenol family which had previously considered as potential

drug candidate for diabetes type 2 patients (Kati et al.,

2010). Besides that, overall viewing Fig. 1, the line of 11b-HSD1 stayed in highest level in most of the case. It means

that there is stronger interaction of ligand on this protein,

compared to other three receptors. Figure 2 shows 24 of the

27 tested (89 %) were higher than 8 kcal/mol and the

friedelin molecule in the terpenes group had better binding

capacity than the controls. Thus the results provide strong

evidences that 11b-HSD1 is a suitable receptor for diabetestype 2 patients being treated with bioactive compounds

derived from E. hirta.

Fig. 1 Absolute value of binding energy of 27 ligands to 4 receptors.The short name of these ligands was written as QTin Quercetin, QTrin

quercitrin, QTol quercitol, RhNose Rhamnose. RTn Rutin, LDin

Leucocyanidin, MTrin Myricitrin, CyGlu cyanidin-3,5-diglucose,

KRon kaemferon, PeGlu pelargonium-3,5-diglucose, CPhol camphol,

Ngenic Neuchlogenic acid, GQnic 3,4 dio galloy-quinic acid, BGlate

Benzyl gallate, BSrol Betasitosterol, CSrol Campesterol, SSrol

Stigmasterol, DodeAte 12 deoxyphor-13 dodecanoate-20 acetate,

phenylAte 12 deoxyphor-13 phenylacetate-20 acetate, InTate Ingenol

triacetate, RNol Resiniferonol, ARine a-amyrine, BRine b amyrine,Flin Friedelin, TRol Taraxerol, TRone Taraxerone, CyNol

Cycloartenol

Med Chem Res

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11b-HSD1

High binding affinity of the ligand to the receptor (Fig. 2)

was explained clearly by interaction analysis in Fig. 3.

According to the molecular framework, there is a tenable

pharmacophore identified between flavonoid family and

non-flavonoid family (terpenes group). Structure of flavo-

noid contained high number of hydroxyl group which can

form strong hydrogen bonds with receptors. Five molecules

(cyanidin 3,5-O-diglucose, myricitrin, pelargonium 3,5-

diglucose, quercitrin, and rutin) were frequently within

hydrogen contact with residues Tyr 183, Thr 124, and Ala

172. From this observation, three residues seemed to play a

critical role in catalytic activity of 11b-HSD1 (PDB code1XU7). This conclusion is strongly supported by studies on

crystal structures and biochemical of 11b-HSD1 (Malinet al., 2006; David et al., 2005). In Fig. 3dh, the Tyr 183

subunit has an important function in the bonding to the

hydroxyl hydrogen of all five ligands whereas Thr 124

could form close vicinity to the ligand surface, and from

there, the hydrogen bond could be set up between them.

The same kind of interaction also happened in case of Ala

172 but this residue was also within hydrophobic contact

with hydrophobes part on ligand (Fig. 3d, f). Moreover,

cyanidin 3,5-O-diglucose, pelargonium 3,5-diglucose, and

rutin could link to the receptor with a high number of

hydrogen bonds compared to myricitrin and quercitrin.

This action can be explained by the affinity of each ste-

roidal hydroxyl group for the receptor. For example, this

functional group in cyanidin 3,5-O-diglucose could donate

two or three hydrogen bonds with different residues such as

Ser 169, Ser 170, Tyr 183, and Leu 215.

In case of terpenes group which has many hydrophobic

components (CH3 group, benzene ring). Thus, terpenes can

form many hydrophobic interactions with other hydro-

phobic residues in receptors active site. a-amyrine, b-amyrine, and taraxerol seemed to be rich on hydrophobic

contact at position of the methyl group which is non-polar.

The compounds cyanidin 3,5-O-diglucose, pelargonium

3,5-diglucose, and quercitrin were also in contact with this

receptor because of the presence of the benzene ring.

Previous studies using crystal structure analysis have

reported, Ser 261 and Arg 269 are reported as largely

hydrophobic residues in previous study involving crystal

structure analysis (Malin et al., 2006) but in the figures

from our study, these hydrophobic interactions were not

present. Ile 46, Ile 121, Leu 217, Leu 126, Thr 220, Thr

222 were frequently observed in ligandreceptor inter-actions between, so they can be a critical part in binding

pocket.

GFAT

There were similarities in the binding mode of 11b-HSD1 and the steroidal hydroxyl group of cyanidin 3,5-

O-diglucose, myricitrin, pelargonium 3,5-diglucose,

quercitrin, and rutin. All established a hydrogen bond

with GFAT1 (PDB code 2ZJ4) at position of Ser 420,

Ser 376, Gln 421, Thr 375, and Ser 422 in the binding

pocket. This result was validated in previous studies

(Kuo-Chen 2004; Vedantham et al., 2007; Yuichiro

et al., 2009). In particular, pelargonium 3,5-diglucose

was seen to have a similar binding mode to the Glc6P

which is a strong inhibitor of GFAT1 (Vedantham et al.,

2007). Besides that, Fig. 4ac, f, g displayed Thr 425

which was close to not only methyl groups but also to

the hydroxyl groups of a-amyrine, b-amyrine, quercitrin,rutin, and taraxerol.

In addition, all of these ligands had hydrophobic inter-

actions with receptors at positions of residue Leu 673, Val

677, Leu 556, and Thr 425. The mechanism of these

interactions, however, differed among the ligands. a-am-yrine, b-amyrine, myricitrin, and taraxerol developedhydrophobic bonds with the hydrophobic receptor from

methyl group. Meanwhile, the link between the benzene

ring and interested part of receptor was decisive tendency

Fig. 2 Absolute value ofbinding energy between E.

hirtas ligand and 11b-HSD1protein

Med Chem Res

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Fig. 3 Bindingmodesofselectivecompoundswith11b-HSD1.a aamyrine,b b-amyrine, c taraxerol, d myricitrin, e pelargonium 3,5-diglucose, f querci-trin, g rutin, and h cyanidin 3,5-O-diglucose. ac belong to terpenes family

and the rest are members of Flavonoid family. Hydrogen Bond Acceptor

(HBA) was shown asgreen vectors, Hydrogen Bond Donor (HBD) was

drawn as red vectors. Hydrophobic (H) was illustrated as yellow spheres

Med Chem Res

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Fig. 4 Binding modes of selective compounds with GFAT. a a amyrine,b b-amyrine, c taraxerol, d myricitrin, e pelargonium 3,5-diglucose, f querci-trin, g rutin, and h cyanidin 3,5-O-diglucose. ac belong to terpenes family

and the rest are members of Flavonoid family. Hydrogen Bond Acceptor

(HBA) was shown as green vectors, Hydrogen Bond Donor (HBD) was

drawn as red vectors. Hydrophobic (H) was illustrated as yellow spheres

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Fig. 5 Binding modes of selective compounds with PPM1B. a a-amyrine, b b-amyrine, c taraxerol, d myricitrin, e pelargonium 3,5-diglucose, f quercitrin, g rutin, and h cyanidin 3,5-O-diglucose. ac belongto terpenes family and the rest are members of Flavonoid family. Hydrogen

Bond Acceptor (HBA) was shown as green vectors, Hydrogen Bond

Donor (HBD) was drawn as red vectors. Hydrophobic (H) was illustrated

as yellow spheres

Med Chem Res

123


Fig. 6 Binding modes of selective compounds with SIRT6. a aamyrine, b b amyrine, c taraxerol, d myricitrin, e pelargonium 3,5-diglucose, f quercitrin, g rutin, and h cyanidin 3,5-O-diglucose. ac belong to terpenes family and the rest are members of Flavonoid

family. Hydrogen Bond Acceptor (HBA) was shown as green vectors,

Hydrogen Bond Donor (HBD) was drawn as red vectors. Hydropho-

bic (H) was illustrated as yellow spheres

Med Chem Res

123


in cyanidin 3,5-O-diglucose, pelargonium 3,5-diglucose,

quercitrin, and rutin.

PPM1B and SIRT6

PPM1B (PDB code 2P8E) had low binding affinity to

ligand when compared to 11b-HSD1, GFAT, and SIRT6but not compared to rutin. This could be explained first by

a low number of bonds between the ligand and the recep-

tor. a-amyrine, b-amyrine, cyanidin 3,5-O-diglucose, andpelargonium 3,5-diglucose are good illustrations. The

binding energy of a-amyrine to 11b-HSD1, GFAT, SIRt6,and PPM1B was -11.5, -9.6, -10.4, -8.6 (kcal/mol),

respectively, and the numbers of bonds for their ligand

interaction with the receptor were 23, 12, 11, and 8,

respectively. Moreover, the number of hydrophobic and

hydrogen bonds was also significantly reduced in the

arrangement from 11b-HSD1 to PPM1B. For rutin, thetotal number of bonds in PPM was lower than GFAT but

higher than 11b-HSD1 and SIRT6. However, bindingaffinity did not follow this pattern and to understand this

finding required a molecular dynamic (MD) and hydrogen

bond analysis step to show. The duration time of the

interaction between ligand and receptor is high frequency

of residues Ala 197, Leu 196, Asp 286, Asp 60, and Asn

287 seemed to play an important role in binding at mode of

PPM1B (Fig. 5). This result differed to Shi (2009) result

which showed Asp 119, Asp 231, Asp 34, Asp 18, Arg 13,

and Gly 35 as the key residue in binding site. This differ-

ence can be explained due to different in chain we tested

on.

By describing the crystal structure of SIRT6 (PDB code

3K35), Fig. 6 revealed the different positions of each

ligand in the binding pocket of 8. Figure 6e, g, h supported

this finding. Although there is similarity in the structure of

the molecules, three compounds bound to different residues

with different mechanisms. The benzene ring in cyanidin

3,5-O-diglucose and rutin contacted Trp 255 and Ala 56

through hydrophobic interaction, but in pelargonium 3,5-

diglucose, the Trp 186 had this function. The hydroxyl

group of the benzene ring in Fig. 6h was the HBD to Thr

55, in contrast with HBA of Tyr 255 in Fig. 6g. From this,

SIRT6 is seen to have a high number of residue which

could form interactions with the functional group of the

ligand. However, most of ligand could link with Trp 186

and Leu 184 which was previously found by Patricia et al.

(2011) in their study of the structure and biochemical

function of SIRT6.

In SIRT6, the total number of bonds did not used to

explain the differences in binding affinity among the three

other receptors in most of situation. For example, there

were 11 bonds between rutin and SIRT6, this number was

lower than 16 bonds in GFAT and 13 bonds in PPM1B but

rutin had a stronger binding affinity to SIRT6 with -10

(kcal/mol) in binding affinity which was lower than -8.6

(kcal/mol) in GFAT and -8.6 (kcal/mol) in PPM1B. This

result for rutin can, however, be explained by MD and

hydrogen bond analysis in PPM1B. These analysis will

figure out stable hydrogen bond and hydrophobic interac-

tion between ligands and receptors.

Conclusion

Docking simulation of 27 drug candidates extracted from

E. hirta showed that the flavonoid and terpenes families

including cyanidin 3,5-O-diglucose, myricitrin, pelargo-

nium 3,5-diglucose, quercitrin, rutin, a-amyrine, b-amy-rine, and taraxerol have high binding affinity to all four

interested receptors which are strongly relevant to diabetes

type 2 in humans. These binding results were shown by

LigandScout to consist of a high number of hydrogen bond

and hydrophobic interactions. However, with the differ-

ences in pharmacophore features, the flavonoid family

shows more advantages in binding to these receptors than

terpenes due to relatively strong hydrogen bonds. The

binding pocket of each receptor: Tyr 183, Thr 124, Ala

172, Ile 46, Ile 121, Leu 217, Leu 126, Thr 220, Thr 222 in

11b-HSD1, Ser 420, Ser 376, Gln 421, Thr 375, Ser 422,Leu 673, Val 677, Leu 556, Thr 425 in GFAT1, Ala 197,

Leu 196, Asp 286, Asp 60, Asn 287 in PPM1B and Trp 186

and Leu 184 in SIRT6 is in agreement with the previous

research. Moreover, five molecules from the flavonoid

family have the polyphenol structure indirectly confirming

the strong capacity of the polyphenol family as a treatment

for diabetes type 2 (Kati et al., 2010). Also the binding

affinity of three of the terpenes compounds also suggest

that this family is also a good prospect for the treatment of

type 2 diabetes. Finally, the comparison of the binding

affinity among the four receptors indicates that 11b-HSD1is the best receptor for accepting of these bioactive com-

pounds derived from E. hirta.

This study has partially demonstrated the effect of E.

hirta on some proteins relating to diabetes type 2. By

calculating the binding energy and pharmacophore mod-

eling, we have obtained the list of 8 promising compounds

in E. hirta. However, further research, using the MD to

determine more accurate binding affinities and the stability

of ligandproteins interactions, is highly suggested. In

addition, experiment study to determine the concentration

of these compounds in E. hirta extraction and their anti-

diabetic activity should be done for drug formulation.

Acknowledgments This research was funded by the Ho Chi MinhInternational University-Vietnam National University. The comput-

ing resources and support by the Institute for Computer Science and

Med Chem Res

123


Technology (ICST) at the Ho Chi Minh City were gracefully

acknowledged.The authors wish to thank Prof. Ho Thanh Phong for

his encouragements and Dr Gay Marsden for proof reading our

manuscript.

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An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophoreAbstractIntroductionMaterial and methodologyMolecular dockingReceptorBioactive compounds in E. hirtaDocking simulations


Result and discussionFree energy binding of bioactive compound to targeted protein related to diabetes type 2Pharmacophore modeling11 beta -HSD1GFATPPM1B and SIRT6

ConclusionAcknowledgmentsReferences

an investigation of antidiabetic activities

Documents

hirta linn andtargeted

keywords diabetes type

euphorbiahirta linn

diabetes patients

protein phosphatase

hydrogen bond acceptor

process involvedthe

theaccepted manuscript