Molecular Docking Studies of Novel 3-Substitued ...

International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

______________________________________________________________________Research Paper

Molecular Docking Studies of Novel 3-Substitued Phenyl-2-(furan-2-yl)4H- Chromen-4-ones as Inhibitors of Interleukin-13 for Asthma Pallavi Gangwara*, Kumaran Santhalingama, Shiny Georgeb, Meena Chandranb, M.Gururagavana aGensilico

Biosolutions, Zamin Pallavaram, Chennai, Tamil Nadu, India, 600043

bDepartment

of Pharmaceutical Chemistry, School of Pharmaceutical Sciences,

Vels University, Pallavaram, Chennai, Tamil Nadu, India, 600117 ___________________________________________________________________________________________ Abstract The present paper describes the molecular docking studies of novel 3-substitued phenyl-2-(furan-2-yl)-4Hchromen-4-ones as inhibitors of interleukin-13 for asthma. IL-13 is a key proinflammatory cytokine in asthma and causes subepithelial fibrosis, a characteristic feature of asthma. Docking studies of 3-substitued phenyl-2(furan-2-yl)-4H-chromen-4-ones have been carried out in the active site of IL-13 by using Argus Lab. Pymol software was used to view the structure and calculating the length of hydrogen bond. The protein file of IL-13 [ PDB code: 1IJZ] was taken from the protein data bank. The lead moiety luteolin from Hygrophila spinosa has shown best ligand pose -6.53048 kcal/mol. All the derivatives of luteolin have shown best ligand pose energy between -8.2043 kcal/mol to -11.789 kcal/ mol. Among them 3-benzoyl-2-(furan-2-yl)-4H-chromen-4-one (5A), 3-(3-bromobenzoyl)-2-(furan-2-yl)-4H-chromen-4-one (5B), 3-(3-bromobenzoyl)-7-hydroxy-2-(5methylfuran-2-yl)-4H-chromen-4-one (5G) has shown best ligand pose like -11.0282 kcal/mol, -11.769 kcal/mol, -11.7896 kcal/mol with IL-13 respectively. The theoretical results have shown a higher estimated binding energy of 3-substitued phenyl-2-(furan-2-yl)-4H-chromen-4-ones suggesting a better anti-asthma activity and efficient inhibitor to treat asthma. Key words: Interleukin-13, asthma, chromone, argus lab.

___________________________________________________________________________________________ INTRODUCTION Asthma affects >14 million people in the United States1. The prevalence of asthma in the United States increased by 74.9% from 1980 to 1996.1 For reasons that are not entirely clear, certain ethnic groups are disproportionately represented in this trend of increasing asthma morbidity2–4. Poverty, which is a common condition among ethnic minority groups with a high prevalence of asthma,5,6 is associated with environmental risk factors for asthma morbidity (eg, cockroach allergen exposure)7 and inadequate access to health care. Our understanding of asthma pathogenesis has changed dramatically with time. Asthma was a chronic inflammatory disorder of the airways mediated by a multitude of cell types and inflammatory mediators. Mast cells and eosinophils were initially believed to play a central role in driving the airway inflammation associated with asthma; however, the emphasis has now shifted to _______________________________________ *Address for correspondence: E-mail: [email protected]

Vol. 2 (3) Jul – Sep 2011

T lymphocytes. In particular, helper T type 2 (Th2) cells (a subset of T cells) are believed to play a central role in initiating and orchestrating the asthmatic airway inflammatory response8. Bronchial asthma is a complex disorder that is thought to arise as a result of aberrant Tlymphocyte responses to noninfectious environmental antigens. In particular, the symptoms of asthma are closely associated with the presence of activated T-helper 2 cell (Th2) cytokine-producing cells interleukin (IL)-4, IL-5, IL-9, and IL-13 in the airway wall. Although each of the Th2 cytokines likely contributes to the overall immune response directed against environmental antigens, a substantial body of evidence points to a singular role for IL-13 in the regulation of the allergic diathesis9. Such mechanisms include IgE production, mast cell differentiation, and eosinophil growth, migration, and activation. A major advance in our understanding of the immunopathogenesis of chronic inflammatory

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disorders such as asthma occurred when it was appreciated that the type of response that is generated by an antigen is influenced greatly by the types of T cells that accumulate at the site of local antigen deposition10. Interleukin (IL)-4 and IL-13 are key proinflammatory cytokines in asthma. The Th2 cytokines interleukin (IL)-4 and IL-13 are thought to play critical roles in the airway inflammation and hyperresponsiveness that characterize asthma. Recent evidence indicates that IL-13 can mediate these effects by acting directly on airway epithelial cells11. IL-13 is a cytokine that is produced by different T-cell subsets and dendritic cells. IL-13 shares many biologic activities with IL-4. This is due to the fact that IL13– and IL-4–receptor complexes share the IL-4– receptor α-chain, which is important for signal transduction. T cells do not express functional IL13 receptors. This is the reason why IL-13, in contrast to IL-4, fails to induce T h2 -cell differentiation, one of the hallmarks of the allergic response. However, IL-13 is required for optimal induction of IgE synthesis, particularly in situations in which IL-4 production is low or absent. On the other hand, IL-13 inhibits proinflammatory cytokine and chemokine production in vitro and has potent anti-inflammatory activities in vivo. From these observations, it can be concluded that IL-13 is an anti-inflammatory cytokine that plays a unique role in the induction and maintenance of IgE production and IgE-mediated allergic responses12. Plants used in organized traditional medical systems. Ayurveda, Unani, Kampo and traditional Chinese medicine have flourished as systems of medicine in use for thousands of years. Their individual arrangements all emphasize education based on an established, frequently revised body of written knowledge and theory. These systems are still in place today because of their organizational strengths, and they focus primarily on multi component mixtures13. Chromone derivatives are abundant in nature and possess a wide range of biological and pharmacological activity14. Chromones are studied as antioxidants15, substances that favor healing of wounds16 and ulcers17, immunostimulators18 and as anti-HIV agents19. Luteolin is a chromone derivative found in Hygrophila spinosa used in the treatment of inflammation, Rheumatism, Gout, Hepatic Obstruction and Jaundice 20-24. In the present study we attempt a theoretical study of chromone derivatives (1A-1J) by docking, to inhibit IL-13, to identify the binding energy for chromone derivatives. Materials and Methods: The Structure of the Protein Interleukin-13 with the PDB ID was retrieved from the Protein Data Bank. Vol. 2 (3) Jul – Sep 2011

ISSN: 2229-3701

It is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleicacids. After obtaining the structure from Protein Data Bank, the possible binding sites of Protein Interleukin-13 were searched using Q-site Finder. These include pockets located on protein surfaces and voids buried in the interior of proteins. Q-site Finder includes a graphical user interface, flexible interactive visualization, as well as on-thefly calculation for user uploaded structures. A series of chromones were obtained as per the scheme of Krayushkin et al25 and used as ligand. The inhibitor and target protein was geometrically optimized and docked using the docking engine Argus Dock. (http://www.arguslab.com/). Argus Lab consists of a user interface that supports OpenGL graphics display of molecule structures and runs quantum mechanical calculations using the Argus compute server. Results and Discussion: Molecular modeling (docking) study was carried out for series of chromone (5A-5J) (Fig: 1, 2) for IL -13 (Fig: 3). The potential active site amino acids of IL- 13 were predicted using Q-site finder. Among the 80 active sites predicted, pocket found to be the best active site which contains 45 amino acids. The Fig.4 shows the active site of the target protein which has the surface area of 796.6 cubic angstroms and volume of 775.8cubic angstroms. Thus, the protein was targeted against pocket 1. Given the three-dimensional structure of a target receptor molecule usually a protein; chemical compounds having potential affinity toward sit are designed rationally, with the aid of computational methods. The target protein and inhibitors were geometrically optimized. All the ten chromone inhibitors were docked against active site of the target protein using Argus lab which gives an insight into the binding modes for the various inhibitors. Out of 10 inhibitors analyzed (i.e. 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J) 5I has showed best binding energy of -11.789 Kcal/mol with 1 hydrogen bond against the target protein. The binding energy of all the inhibitors was shown in Table-1. Figure 5 represents the best docked complex of the inhibitor 5I to that of the target protein. Conclusion: We analyze the various chromone derivatives obtained from the modification of Luteolin which is having anti-inflammatory and anti-bronchitis activity present in plant Hygrophila spinosa. Further these derivatives were docked with IL-13 protein by using argus lab to get best hits. 5I showed the highest affinity towards IL-13 than other compounds. This creates a strong hypothesis that the effect of complex formation by IL-13 and chromone derivatives represents the hydrogen www.ijrpbsonline.com

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ISSN: 2229-3701

bonding interaction between the 5I and target molecule. Thus we can conclude that the compounds having chromone derivatives could act as a best drug for the treatment of asthma.

Figures:

O

HO O

-

Ar

O

OH

HO R

O

,

O R1

OH

Fig:1 Luteolin

Ar:

O

Fig:2 Chromone derivatives (1A-1J)

Br ,

Cl

,

NO2

,

OCH3 , R: H, -OH, R : H, -CH 1 3

Fig:3

Protein structure of IL-13

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Predicted active site using Q-site finder Fig : 5

Hyrogen bond between IL-13 & 5I TABLE: 1 Summary of binding energy of all

inhibitors against the target IL -13 protein

S.No

Name of the drugs

No of conformation

Binding Energy

Hydrogen bonds

a

Luteolin

141

-6.53048

1

1

5A

140

-11.0282

1

2

5B

140

-11.769

1

3

5C

140

-10.082

1

4

5D

140

-8.20434

3

5

5E

150

-9.03418

1

6

5F

140

-10.9465

NIL

7

5I

140

-11.7896

1

8

5J

140

-10.9712

1

9

5K

140

-8.4501

1

10

5L

140

-8.49725

1

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