Available online www.jocpr.com

Journal of Chemical and Pharmaceutical Research, 2014, 6(9):278-281

Research Article

ISSN : 0975-7384
CODEN(USA) : JCPRC5

Computational studies on the antiobesity effect of polyphenols frompomegranate leaf
Sudeep H. V.* and Shyam Prasad K.
Department of Biomedicinal Research, Vidya Herbs Pvt. Ltd, #101, Jigani II phase, Bangalore, Karnataka, India_____________________________________________________________________________________________
ABSTRACT
Different polyphenols present in Pomegranate leaves were docked into validated drug targets of obesity which
include enzymes pancreatic lipase and fat mass and obesity associated protein (FTO). The in silico calculations
predicted that lowest energy docked poses of phenolic compounds can interact with catalysis-dependent residues,
thus making them possible catalytic inhibitors and of course physiologically active. Compounds that possess anumber of hydrogen-bond-accepting and/or -donating groups like phenolics and quinones show extensive
interactions with the targets. Based on the ligand-protein interaction we can conclude that phenolic principles like
Punicalagin, corilagin, punicalin and apigenin thus offer profound promise as anti-obesity drugs. This study has
immediate applications in development of non-toxic drugs/nutraceuticals that may safeguard human populations
against severe complications associated with obesity.
Key words: Docking, Obesity, Pomegranate, Polyphenols_____________________________________________________________________________________________INTRODUCTION
Weight gain and obesity are major risk factors for the health complications ranging from insulin resistance and type2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease[1]. Physiologically, obesity
is a disarray of energy balance and primarily considered as a disorder of lipid metabolism[2]. The condition isassociated with a growing number of enzymes involved in lipid metabolic pathways. They represent a rich pool ofpotential therapeutic targets for obesity[3][4].
Pancreatic lipase is a key enzyme involved in obesity responsible, in conjunction with a pancreatic colipase, for thebreakdown of dietary triglcerides into the absorbable fatty acids and monoglycerides. Orlistat is anti-obesity drugthat binds to the active site of lipase and inhibit its activity. The complex induces a conformational change in theenzyme that leads to a lid-like structure on the lipase, hence exposing the catalytic active site. This operation leads toacylation of a hydroxyl group on serine residue burden on the active site of the enzyme making it inactive as lipase.
The inactivated lipase is unable to hydrolyse fats into fatty acids and monoglycerides, which lead to their passagewith faeces. This inhibition decrease the absorption of fats by >30 % [5].
Fat mass and obesity associated protein also known as alpha-ketoglutarate-dependent dioxygenase (FTO) is anotherenzyme that appears to be correlated with obesity in humans [6]. FTO contributes to the regulation of the global
metabolic rate, energy expenditure and energy homeostasis. FTO contributes to the regulation of body size and body
fat accumulation.
Pomegranate (Punica granatum L.) is a shrub cultivated in India, Mediterranian countries, Malaysia, tropical Africa
and to some extent in United States [7]. The plant has been valued since ancient times to treat many conditions suchas diarrhea, dysentery, hemorrhage, parasitic infections, ulcers and microbial infections [8]. Pomegranate is a richsource of polyphenols and possesses an array of compounds that have been attributed to the pharmacological278

Sudeep H. V. and Shyam Prasad K.
J. Chem. Pharm. Res., 2014, 6(9):278-281______________________________________________________________________________
activities such as anti-tumor, astringent and antidiarrheal activities. The present research carried out at Vidya Herbs
Pvt Ltd encompasses the evaluation of therapeutic potentials of phenolic compounds from P. granatum leaves by insilico molecular docking with key regulatory enzymes involved in lipid metabolism viz., pancreatic lipase and FTO.
EXPERIMENTAL SECTION
AutoDock tools was utilized to generate grids, calculate dock score and evaluate the conformers of inhibitors boundin the active site of enzymes pancreatic lipase and FTO as targets for antiobesity activity. Automated docking is agraphical user interface. AutoDock 4.2 was employed to get docking and binding scores; which is implemented by
Lamarckian genetic algorithm method. The ligand molecules i.e., the phenolic compounds from pomegranate leaf
(Figure 1) and standard drug Orlistat were designed and the structure was analyzed using ACD/Chemsketch. ThePRODRG server was used to minimise energy of drug compounds and 3D coordinates were prepared. The protein
structure files (PDB ID: 1LPB and 3LFM) were taken from PDB and edited by removing the hetero atoms using
Python molecule viewer. The grid map was centred at particular residues of the protein and was generated withAutoGrid. As per genetic algorithm all the torsions were allowed to rotate during docking. The Lamarckian genetic
algorithm and the pseudo-Solis and Wets methods were applied for minimization, using default parameters [9].
Figure 1. Structures of docked polyphenols discussed in this work
OH

OH

OHO

HO

OH

O
HO

O

O

OH
OH

OH

O

OH

ApigeninO

Luteolin 4-O-glucopyranoside
OH
OH

O

O

O

OH

O

OH
O

O

HOOH

HOO
HOHO

O

OH

HOO

O

HOOH

HO

O

OH

OH

HOO

O
O

O
OH
OH

Corilagin

Ellagic acid
OH HO

HO

Brevifolin carboxylic acid
OH

OH

O

OH
HO

O
O
HO

OH

O

O

O

O

HO

O
O

O

OH

OH

HO

O

O

O
O

HO

OH

HO
OH

OH
O

HO

OH

HO

O

OH

O

O

OH

OH
O
O

O
O
OH

HO
HO

Punicalin

OH HO

OH

Punicalagin
RESULTS AND DISCUSSION

Extracts of pomegranate leaves have been previously documented to possess anti-obesity activity [10].
Phytochemically it is a rich source of polyphenols. Further it is well known that flavanoids and tannins are major279

Sudeep H. V. and Shyam Prasad K.
J. Chem. Pharm. Res., 2014, 6(9):278-281______________________________________________________________________________
group of secondary metabolites in plant kingdom and attribute to the medicinal claims of the plants [11][12]. This
work presents the molecular docking of polyphenols from pomegranate leaves with the key metabolic enzymes
responsible for obesity with a view of obtaining structural motifs that preferentially interact with these molecules.
The docking results revealed compounds with more favorable interactions with the targets and also indicated thatsome of the compounds present certain structural motifs that could make them form extensive Van der Waals
interactions and hydrogen bonding with targets. After comparative docking analysis it was learnt that punicalaginand corilagin showed better inhibition of enzymes in comparison to other compounds.
All the test compounds showed favourable interactions with pancreatic lipase better than the standard drug orlistat(Table 1). Extensive interactions were observed between punicalagin and Asn residues 229, 384, Arg residues 337,339, Asp 387 and Tyr369 residues of pancreatic lipase with a value of -11.85 and seven hydrogen bonds (Figure 2).
The orientation of polyphenols in the catalytic site of FTO indicated profound interaction in the form of proteinligand hydrogen bond formation (Table 2). Among the tested molecules, corilagin exhibited top pose with low
binding energy (-9.44 kJmol-1) and forming nine hydrogen bonds with active pocket residues; Asp467, Gln468,Arg80, Pro93, Ser95 and Ala466 (Figure 3).
Figure 2. (A) Predicted hydrogen bonding interactions (green spheres) can be seen between punicalagin and active residues of pancreaticlipase (B) Binding of Punicalagin with active pocket of Pancreatic lipase

A

B

Figure 3. (A) Some predicted interactions (blue spheres) between Corilagin (green and white) and active site residues Asp467, Gln468,Arg80, Pro93, Ser95, Ala466 of FTO; (B) Corilagin in the active site of FTO

AAB

B B280Sudeep H. V. and Shyam Prasad K.
J. Chem. Pharm. Res., 2014, 6(9):278-281______________________________________________________________________________
Table1. In silico docking score of polyphenols from P. granatum leaf and Orlistat with Pancreatic lipase

Molecule
Punicalagin
Ellagic acid
Corilagin
Brevifolin COOH
Punicalin
Eapigenin
Luteolin 4-O-glucopyranoside
Orlistat (Std)Binding
Energy(kJ/mol)-11.85
-7.07
-7.81
-6.44
-8.2
-7.11
-8.18
-1.03

LigandEfficiency(kJ/mol)
-0.15
-0.32
-0.17
-0.31
-0.15
-0.36
-0.26
-0.03

Inhibitory
constant(µM)
2.06
6.59
1.9
19
971.986.13
1.01
176.96

HBondInteraction

756
57
54
2

Asn384, Tyr369,Arg337, Asn229, Asp387, Arg339
Glu370, Arg339, Asp387, Asn384
Asn229, Lys238, Glu15, Cys237, Asn10
Glu370, Asn384, Asp387, Arg339
Asp387, Asp328, Glu13, Glu370, Arg339
Arg44,Cys39, Glu48
Gln368,Asn384, Asp328,Thr292
Lys238

Table 2. In silico docking score of polyphenols from P. granatum leaf and Orlistat with FTO

Molecule
Punicalagin
Ellagic acid
Corilagin
Brevifolin COOH
Punicalin
Apigenin
Luteolin 4-O-glucopyranoside
Orlistat (Std)Binding
Energy(kJ/mol)
-8.63
-7.21
-9.44
-6.52
-7.97
-8.54
-10.41-4.65

LigandEfficiency(kJ/mol)
-0.11
-0.33
-0.21
-0.31
-0.14
-0.43
-0.34
-0.14

Inhibitory
constant(µM)
469.14
5.18
119.39
16.63
1.44
555.9
23.2
390.87

HBond

Interaction

4493
44
53

Gln468, Asp208, Lys391, Ser95
Asp208, His73, Arg80, Pro93
Asp467, Gln468, Arg80, Pro93, Ser95, Ala466
Arg80, Ser95
Arg80, Ser95, Pro95
Pro93, Leu78, His73, Ser95
Asp208, Arg80, Pro93, Ser95
Arg80, Ser95

CONCLUSION
Inhibitor selectivity remains an important issue when being considered for chemotherapy. Nevertheless, many
pharmacologically active natural polyphenols can contribute as drugs against complications such as obesity anddiabetes, structural differences are now being exploited in drug designing. The docking calculations in this study
revealed that most of the phenolic and quinone compounds with top poses are strong inhibitors of pancreatic lipaserather than FTO. Although these compounds have been shown to have inhibitory action against the tested enzymes,
target-based experimental screening of the compounds will provide information about selectivity and mechanism ofaction.
REFERENCES[1] SE Shoelson; L Herrero; A Naaz, Gastroenterology., 2007, 132(6), 2169-80.
[2] CD Strader; JJ Hwa; M Van Heek; EM Parker, Drug Discovery Today., 1998, 3, 250–256.
[3] Y Shi; P Burn, Nature Reviews Drug Discovery., 2004, 3, 695–710.
[4] I Melnikova; D Wages, Nature Reviews Drug Discovery., 2006, 5, 369–370.
[5] PA Hollander; SC Elbein; IB Hirsch; B Kelly; J McGill; T Taylor, Diabet Care., 1998, 21, 1288-301.
[6] TM Frayling; NJ Timpson; MN Weedon; E Zeggini; RM Freathy; CM Lindgren; JR Perry; KS Elliott; H Lango;
NW Rayner; B Shields; LW Harries; JC Barrett; S Ellard; CJ Groves; B Knight; AM Patch; AR Ness; S Ebrahim;
DA Lawlor; SM Ring; Y Ben-Shlomo; MR Jarvelin; U Sovio; AJ Bennett; D Melzer; L Ferrucci; RJ Loos; IBarroso; NJ Wareham; F Karpe; KR Owen; LR Cardon; M Walker; GA Hitman; CN Palmer; AS Doney; ADMorris; GD Smith; AT Hattersley; MI McCarthy, Sci., 2007, 316(5826), 889–94.
[7] M Viuda-Martos; J Fern_andez-L_opez; JA Perez-Alvarez, Compr Rev Food Sci Food Saf., 2010, 9, 635–54.
[8] YG Lihua Zhang; Y Zhang; J Liu; J Yu, Sci Horticult., 2010, 123, 543–6.
[9] A Rodriguez; D Infante, Characterization in silico of flavonoids biosynthesis in Theobroma cacao L. Net Biol.,2011, 1, 34-45.
[10] IK Adnyana; EY Sukandar; Ari Yuniarto; S Finna, Int J Pharm Pharmaceut Sci., 2014, 6(4), 626-631.
[11] V Koleckar; K Kubikova; Z Rehakova; K Kuca; D Jun; L Jahodar; L Opletal, Med Chem., 2008, 8, 436-447.
[12] T Hirano; M Gotoh; K Oka, Life sci., 1994, 55, 1065-1069.

281