DSpace at VNU: An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophore

DSpace at VNU: An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecula...

MEDICINAL CHEMISTRY RESEARCH Med Chem Res (2014) 23:2033–2045 DOI 10.1007/s00044-013-0794-y ORIGINAL RESEARCH An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophore Quy Trinh • Ly Le Received: 20 May 2013 / Accepted: 12 September 2013 / Published online: October 2013 Ó Springer Science+Business Media New York 2013 Abstract Herbal remedies have been considered as potential medication for diabetes type 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 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 dehydrogenase type 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 interested proteins of this article The substances are quercetrin, rutin, myricitrin, cyanidin 3,5-O-diglucoside, pelargonium 3,5diglucose in ‘‘flavonoid family’’ and a-amyrine, b-amyrine, Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0794-y) contains supplementary material, which is available to authorized users Q Trinh Á L Le School of Biotechnology, International University–Vietnam 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: ly.le@hcmiu.edu.vn taraxerol in ‘‘terpenes group.’’ The result can be explained by the 2D picture which showed hydrophobic interaction, hydrogen bond acceptor, and hydrogen bond donor forming 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 Keywords Diabetes type Á Euphorbia hirta Linn Á Molecular docking Á 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 (International 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 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 normal 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 Determination of the best treatment for diabetes type is complicated because this is a progressive disease Currently, insulin combined with other drugs is the preferred 123 2034 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 Pelargonium 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 proteins to determine which compound is an effective binder E hirta contains three families of biomolecular compounds such as tannin, flavonoid, and terpenes (Mohammad et al., 2010; Sandeep and Chandrakant, 2011) Tannin and flavonoid are strong antioxidants (Pietta, 2000; Rield and Hagerman, 2001) Quercitrin, one compound in Flavonoid group, was good illustration In the thiobarbituric acid (TBA) experiment quercitrin showed strong antioxidant activity, giving 92.5 % inhibition and the IC50 was calculated to 23.40 lM (Basma et al., 2011) Products of oxidation have been shown to play an essential role in the pathogenesis of diabetes type and (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 Several proteins which were involved in glucose metabolism consequently related to diabetes type From our intensive review on targeted proteins for antidiabetic drug development (Trang and Ly, 2012), these important target proteins including 11-b hydroxysteroid dehydrogenase type (11b-HSD1), Glutamine fructose-6-phosphate 123 Med Chem Res (2014) 23:2033–2045 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 proteins relating to diabetes type 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 (PDB code 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 observations with new ligand In view of this, 11b-HSD1 (PDB code 1XU7) was tested again with molecule: NADPH dihydro-nicotinamide-adenine-dinucleotide phosphate; GFAT (PDB code 2ZJ4) was tested with 2-deoxy-2amino 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 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, optimized 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 Docking simulations The docking process was done using Autodock Vina (Oleg and Arthur, 2009) Autodocktool, one section in Molecular Graphic Laboratory, 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 Quercitrin Rutin Pelargonium 3,5-diglucose Quercetin Cycloartenol Cyanidin 3,5-O-diglucoside Table 2D structures of 27 drug candidates suggested from NCBI Kaemferon Leucocyanidin Quercitol Camphol Myricitrin Rhamnose Med Chem Res (2014) 23:2033–2045 2035 123 3.4-di-O-galloyquinic acid Stigmasterol Ingenol triacetate Neuchlogenic acid Beta sitosterol Resiniferonol Table continued 123 12-Deoxy-phorbol-13-dodecanoate-20-acetate a-Amyrine b-Amyrine Campesterol 12-deoxy-phorbol-13-phenylacetate-20-acetate Benzyl gallate 2036 Med Chem Res (2014) 23:2033–2045 Med Chem Res (2014) 23:2033–2045 2037 Table Position of the Grid box center in four protein molecules Protein molecule PDB code ˚) X, Y, Z coordination (A Friedelin 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 Fig 7) The site of Grid Box is illustrated in Table 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 program The content of configure file was determined as position of receptor file, ligand file, data of Grid-box’s three coordinates (Table 2), the size of Gridbox which was set up in 30 30 30 points, number of modes which were ten, and the energy range which was set up at kcal/ mol Taraxerone Pharmacophore modeling This part of process was carried out using the pharmacophore 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 Taraxerol Table continued Free energy binding of bioactive compound to targeted protein related to diabetes type In order to investigate the binding capacity of bioactive compounds in E hirta Linn on proteins related to diabetes type in humans, we docked the compounds to the proteins 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, friedelin, taraxerol, taraxerone, and cycloartenol showed the best results All receptor for terpenes group had particularly 123 2038 Med Chem Res (2014) 23:2033–2045 high binding affinities with the highest at 11b-HSD1 (PDB code 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 11bHSD1 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 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-amyrine, b-amyrine, and taraxerol The high binding efficiency is 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, cyanidin 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 (quercitol, rhamnose, and camphol) which had the lowest binding affinity The absolute value for these three ligands is shown sequentially in Table They all share a simple structure with only one ring and few hydroxyl groups outside which may explain their low binding affinity Thus, these molecules 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 low interaction with PPM1B Neuchlogenic acid and 3,4 dio galloy-quinic acid are illustrated in supplementary Table 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), the other five are members of flavonoid family (quercitrin, rutin, myricitrin, cyanidin 3,5-O-diglucoside, and pelargonium 3,5-diglucose) Five of them have structure of polyphenol family which had previously considered as potential drug candidate for diabetes type patients (Kati et al., 2010) Besides that, overall viewing Fig 1, the line of 11bHSD1 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 shows 24 of the 27 tested (89 %) were higher than 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 diabetes type patients being treated with bioactive compounds derived from E hirta Fig Absolute value of binding energy of 27 ligands to 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 123 Med Chem Res (2014) 23:2033–2045 2039 Fig Absolute value of binding energy between E hirta’s ligand and 11b-HSD1 protein Pharmacophore modeling 11b-HSD1 High binding affinity of the ligand to the receptor (Fig 2) was explained clearly by interaction analysis in Fig According to the molecular framework, there is a tenable pharmacophore identified between flavonoid family and non-flavonoid family (terpenes group) Structure of flavonoid contained high number of hydroxyl group which can form strong hydrogen bonds with receptors Five molecules (cyanidin 3,5-O-diglucose, myricitrin, pelargonium 3,5diglucose, 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 code 1XU7) This conclusion is strongly supported by studies on crystal structures and biochemical of 11b-HSD1 (Malin et al., 2006; David et al., 2005) In Fig 3d–h, 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 steroidal 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 hydrophobic residues in receptors’ active site a-amyrine, bamyrine, 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 ligand–receptor interactions between, so they can be a critical part in binding pocket GFAT There were similarities in the binding mode of 11bHSD1 and the steroidal hydroxyl group of cyanidin 3,5O-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 4a–c, 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 interactions 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-amyrine, b-amyrine, myricitrin, and taraxerol developed hydrophobic bonds with the hydrophobic receptor from methyl group Meanwhile, the link between the benzene ring and interested part of receptor was decisive tendency 123 2040 Fig Binding modes of selective compounds with 11b-HSD1 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 a–c belong to terpenes family 123 Med Chem Res (2014) 23:2033–2045 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 (2014) 23:2033–2045 Fig Binding modes of selective compounds with GFAT 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 a–c belong to terpenes family 2041 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 123 2042 Fig Binding modes of selective compounds with PPM1B a aamyrine, b b-amyrine, c taraxerol, d myricitrin, e pelargonium 3,5diglucose, f quercitrin, g rutin, and h cyanidin 3,5-O-diglucose a–c belong to terpenes family and the rest are members of Flavonoid family Hydrogen 123 Med Chem Res (2014) 23:2033–2045 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 (2014) 23:2033–2045 Fig Binding modes of selective compounds with SIRT6 a a amyrine, b b amyrine, c taraxerol, d myricitrin, e pelargonium 3,5diglucose, f quercitrin, g rutin, and h cyanidin 3,5-O-diglucose a– c belong to terpenes family and the rest are members of Flavonoid 2043 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 123 2044 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 SIRT6 but not compared to rutin This could be explained first by a low number of bonds between the ligand and the receptor a-amyrine, b-amyrine, cyanidin 3,5-O-diglucose, and pelargonium 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, the total number of bonds in PPM was lower than GFAT but higher than 11b-HSD1 and SIRT6 However, binding affinity 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 difference can be explained due to different in chain we tested on By describing the crystal structure of SIRT6 (PDB code 3K35), Fig revealed the different positions of each ligand in the binding pocket of 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 3,5diglucose, 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 123 Med Chem Res (2014) 23:2033–2045 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 interaction 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, pelargonium 3,5-diglucose, quercitrin, rutin, a-amyrine, b-amyrine, and taraxerol have high binding affinity to all four interested receptors which are strongly relevant to diabetes type in humans These binding results were shown by LigandScout to consist of a high number of hydrogen bond and hydrophobic interactions However, with the differences 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 (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 diabetes Finally, the comparison of the binding affinity among the four receptors indicates that 11b-HSD1 is the best receptor for accepting of these bioactive compounds derived from E hirta This study has partially demonstrated the effect of E hirta on some proteins relating to diabetes type By calculating the binding energy and pharmacophore modeling, we have obtained the list of promising compounds in E hirta However, further research, using the MD to determine more accurate binding affinities and the stability of ligand–proteins’ interactions, is highly suggested In addition, experiment study to determine the concentration of these compounds in E hirta extraction and their antidiabetic activity should be done for drug formulation Acknowledgments This research was funded by the Ho Chi Minh International University-Vietnam National University The computing resources and support by the Institute for Computer Science and Med Chem Res (2014) 23:2033–2045 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 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one compound in Flavonoid group, was good illustration In the... bond and hydrophobic interaction between ligands and receptors Conclusion Docking simulation of 27 drug candidates extracted from E hirta showed that the flavonoid and terpenes families including... demonstrated the effect of E hirta on some proteins relating to diabetes type By calculating the binding energy and pharmacophore modeling, we have obtained the list of promising compounds in E hirta