Murugesan Sathyadevi et al.

/ Journal of Pharmacy Research 2014,8(12),1743-1750

Research Article
ISSN: 0974-6943

Available online through

www.jpronline.info

Aldose reductase inhibitors from the fruits of Physalis peruviana Linn.- An In silico Approach
Murugesan Sathyadevi and Sorimuthu Pillai Subramanian*
Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received on:08-09-2014; Revised on: 19-10-2014; Accepted on:27-11-2014
ABSTRACT
Background: The fruits of Physalis peruviana Linn. have been widely used in the traditional medicine for various ailments. Recently, we
have reported that the oral administration of Physalis peruviana Linn. fruit extract improves insulin sensitivity and ameliorates hyperglycemia in high-fat diet low dose STZ-induced type 2 diabetic rats. Molecular docking, the technique primarily employed for predicting and
analyzing the interactions between protein receptors and ligands, is now an integral aspect in drug discovery and development area. Hence,
the present study was aimed to screen the identified phytoconstituents of Physalis peruviana L. fruit to identify the potent constituent
attributing for its antidiabetic activity using insilico approach. Methods : HPLC analysis of the ethanolic extract of fruits was performed
using Shimadzu HPLC system equipped with a diode array detector. Docking studies on the constituents were carried out using AutoDock
4.2 software against the aldose reductase receptor. Results: HPLC analysis indicated that the major flavonoids present in the fruit extract
include kaempferol, myricetin, quercetin and rutin and their binding energy was found to be -12.89, -12.99,-13.31, -14.84, respectively. The
activity was comparable with fidarestat, a standard drug. Conclusion: The study indicates the presence of biologically active flavonoids in
the fruit extract and their interactions with aldose reductase. The insilico data provide vital clues that can be used to design new molecules
with improved activity for the successful treatment of diabetes mellitus.
KEY WORDS: Physalis peruviana L. fruit, aldose reductase, kaempferol, myricetin, quercetin, rutin.
INTRODUCTION
Molecular docking is an In silco technique widely employed for predicting and analyzing the interactions between protein receptors and
ligands. It provides most detailed possible view of drug receptor interactions and also has created a new rational approach to drug design. Diabetes mellitus (DM), the third leading cause of death in the
world, is a multifactorial, multisystemic, metabolic disorder arises due
to deficiency and/or efficiency of insulin. Most of the currently available drugs for the treatment of diabetes often elicit undesirable side
effects after prolonged use. Hence, search for novel therapeutic agents
without side effects continues. Among the various factors responsible for the initiation and progression of secondary complications in
diabetes, the activation of polyol metabolic pathway was first discovered and in fact is the generally accepted to be the mechanism of
prime importance in the pathogenesis of diabetic complications1.

*Corresponding author.
Dr. S. Subramanian
Associate Professor
Department of Biochemistry
University of Madras
Guindy campus, Chennai 600 025
Tamilnadu, India

Aldose reductase (ALR2, EC 1.1.1.21) is a cytoplasmic, NADPH

dependent monomeric enzyme belongs to the superfamily aldo-ketoreductase (AKR). It contains 315 aminoacids with a molecular weight
of 36K Da. It is found to be present in most human cells 2-4 ALR2
together with sorbitol dehydrogenase (SDH) forms the polyol pathway wherein AR initially catalyzes the NADPH-dependent reduction
of the aldehyde form of glucose to form sorbitol. SDH then utilizes
NAD oxidizes the intermediate sorbitol to fructose 5.
Normally, the cellular glucose is oxidatively metabolized through the
glycolytic pathway and then the Krebs cycle to produce energy for
cells. Under chronic hyperglycemia conditions, however, the increased
amount of glucose activates ALR2 and is metabolized by the activated polyol pathway. The increased flux of the polyol pathway by
chronic hyperglycemia is implicated in the pathogenesis of diabetic
complications including particularly diabetic retinopathy, nephropathy and neuropathy and one of the vital linkages has been proposed
to be an increase in oxidative stress mediated by free radicals.
Biomolecular evidences for the role of the polyol pathway are
recently provided by cellular experiments and regulations of AR
gene expression in the presence of high glucose induction 6,7. Intense

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efforts have been directed towards the development of effective aldose reductase inhibitors, but still only epalrestat is commercially
available and that too only in Japan. Thus, it is becoming of great
importance, novel chemotypes to be developed, lacking the poor
pharmacokinetic profile or the side effects of the ARIs that have
failed to the clinical trials 8.
Our traditional systems of medicines have a wide variety of plant
preparations, which may act as potential drugs or medicines for effective treatment of various diseases. However, most of the medicinal
plants used in the traditional medicine lack scientific scrutiny. Physalis peruviana Linnaeus is one such medicinal plant, widely used herb
in folk medicine for various ailments. It is a native plant from the
Peruvian Andens and now widely distributed throughout the tropical
and sub-tropical countries. The botanical name of the plant is Physali
speruviana L, belonging to the family Solanaceae and genus Physalis 9. In the folk medicine, the fruits are used as a means to improve the
immune system of humans. Wu et al., (2006) 10, have reported that the
ethanolic extract of the fruits possess significant antioxidant properties than the aqueous extract. Furthermore, the antioxidant activity
associated with presence of high levels of polyphenols and significant levels of vitamin A and C. Recently, we have reported the effect
of oral administration of the ethanolic extract of Physalis peruviana
L. fruits in improving Insulin sensitivity and amelioration of hyperglycemia in high fat diet low dose STZ induced type 2 diabetes in
rats11. The present study was aimed to evaluate the inhibitory effect
of myricetin, kaempferol, quercetin and rutin, the major flavonoids
present in the fruit extract against ALR2 activity by molecular docking studies.
MATERIALS AND METHODS
Plant Material
Intact, fruits of Physalis peruviana were collected from Theni,
Tamilnadu, India. The fruits were carefullyselected according to the
degree of ripeness measured by fruit color (brilliant orange).The plants
were identified and authenticated by a qualified taxonomist and a
voucher specimen was deposited at Centre of Advanced Studies in
Botany, University of Madras.

HPLCDAD system for analysis of phenolic compounds

HPLC analysis was performed using Shimadzu HPLC system equipped
with a diode array detector. The chromatographic separations were
performed on an Inertsil C18 analytical column (4.6 250 mm i.d., 5
m). The composition of solvents and the gradient elution conditions used were described previously by Bengoechea et al., (1997)
,Schieber et al., (2001) and Butsat et al., (2009) 12-14 , with some modifications. The mobile phase consisted of purified water with acetic acid
(pH 2.74) (solvent A) and acetonitrile (solvent B) at a flow rate of 0.8
ml/min. Gradient elution was performed as follows: from 0 to 5 min,
linear gradient from 5% to 9% solvent B; from 5 to 15 min, 9% solvent
B; from 15 to 22 min, linear gradient from 9% to 11% solvent B; from 22
to 38 min, linear gradient from 11% to 18% solvent B; from 38 to 43
min, from 18% to 23% solvent B; from 43 to 44 min, from 23% to 90%
solvent B; from 44 to 45 min, linear gradient from 90% to 80% solvent
B; from 45 to 55 min, isocratic at 80% solvent B; from 55 to 60 min,
linear gradient from 80% to 5% solvent B and a re-equilibration period
of 5 min with 5% solvent B used between individual runs. Operating
conditions were as follows: column temperature, 38C, injection volume, 20 l, and UV-diode array detection at 280 nm (hydroxybenzoic
acids), 320 nm (hydroxycinnamic acids) and 370 nm (flavonols) at a
flow-rate of 0.8 ml/min. Spectra were recorded from 200 to 600 nm.
Phenolic compounds in the samples were identified by comparing
their relative retention times and UV spectra with those of authentic
compounds and were detected using an external standard method.
Aldose reductase Molecular docking studies
Protein Preparation
The protein target, which is retrieved from the RCSB Protein Data
Bank (PDB ID: 1PWM) serves as docking receptor. All the bound
ligands and water molecules were removed from the active site of the
receptor. For docking target, crucial amino acids of the active site
were identified using data in pdb sum available in the PDB. The chemical structures of ligands used in the present study were shown in
figure 1.
1

OH

3
5

HO

10
9

Preparation of plant extract

The fruits were dehusked, washed, crushed in an air oven at 50C
then powdered in an electrical grinder, which was then stored in an
airtight brown container at 5 C until further use. The powdered fruits
were delipidated with petroleum ether (60 - 80 C) for overnight. It was
then filtered and soxhalation was performed with 95% Ethanol. Ethanol was evaporated in a rotary evaporator at 40 50 C under reduced
pressure.

8
OH

OH

OH

HO

A. Kaempferol

OH

HO

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HO
O

OH

B. Myricetin
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default parameters. Binding energy, torsional energy, intermolecular
OH
energy, number of H-bonds and RMS value were recorded in each
OH
ligand bound conformations.
HO

RESULTS
The HPLC analysis of the purified fraction of isolated components
have similar retention times (approximately Rutin 6.94 min, Myricetin
11.40 min, Quercetin 9.68 min and Kaempferol 15.97 min) to the Rutin,
Myricetin, Quercetin and Kaempferol standards (Figure 2 and 3).

OH
OH

C. Quercetin
OH

HO

O
OH
OH

HO

OH
O

OH

O
H 3C
O

HO

OH

OH

D. Rutin
Figure 1. HPLC analysis Standard of Rutin, Myricetin, Quercetin
and Kaempferol

Figure 2. HPLC analysis Standard of Rutin, Myricetin, Quercetin

and Kaempferol

Ligand Preparation
The two dimensional structures of ligands were drawn using
ChemDraw Ultra 12.0 and then converted to 3D (.pdb) structures
using Openbabel software tool. Thecrystal structure (PDB ID: 1PWM)
of the standard ligand, (Fidarestat) was taken for molecular docking.
The 3D structures of both ligands and the standard were submitted
to PRODRG server for energy minimization.
Molecular Docking
The molecular docking was performed and analyzed using AutoDock
4.2. A Lamarckian genetic algorithm method implemented in the program suite was employed to identify appropriate binding modes and
conformation of the ligand molecules. Gasteiger charges were added
and the rotatable bonds were set by the AutoDock tools and all
torsions were allowed to rotate. Polar hydrogen atoms were added
and Kollman charges were assigned to the protein using AutoDock
tools (ADT). The grid map was centered at the active site pocket of
the protein by Autogrid. The grid map which was centered at the
following amino acids residues of the protein (Trp20, Tyr40, Trp111
and Leu300) was predicted from the poseview data available in the
PDB site. In all the cases, the grid maps with a grid box size of 60x60x60
3 points with a grid-point spacing of 0.375 was used. During docking, centre grid parameters were specified for x, y and z axis as 16.9, 7.8 and 16.7, respectively. The Lamarckian genetic algorithm, the
pseudo-Solis and Wets methods were applied for minimization using

Figure 3. HPLC analysis of Rutin, Myricetin, Quercetin and

Kaempferol
Auto dock has computed the lowest score for the docking. From the
table 1, it was observed that the docking of the ligands, Kaempferol,
myricetin, quercetin and rutin together with the receptor crystal structure of human aldose reductase and fidarestat shows the atomic
contact energy: Kaempferol(A) -12.89, myricetin (B) -12.99,
quercetin(C) -13.31, rutin(D) -14.84 and native fidarestat (E) -11.54.
From the table 2, it was observed that the ligands with the interacting
residues that shows: Kaempferol (A):TYR48, CYS298,
LEU301,myricetin (B): TYR48, ASN160, TYR209, CYS298, LEU301,
quercetin (C): TYR48, ASN160, TYR209, CYS298, LEU301, rutin (D):
ALA299, LEU300, SER302 and fidarestat(native) (E) : LEU300, SER302

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[ figure 4 (3D Structure) and 5 (2D Structure)].The number of interacting hydrogen bonds are:Kaempferol(A) -5, myricetin(B) - 9,
quercetin(C)- 7, rutin (D) - 7 and native fidarestat(E) -3 ( table 2).
Figure 6 shows the surface of the protein with the ligand binding
packet.
Table 1. Binding free energies for all the ligands with the receptor
Crystal structure of human Aldose Reductase and Fidarestat PDB
ID: 1PWM .
Molecule Name

Estimated Free Energy

of Binding (kcal/mol)

Kaempferol
Myricetin
Quercetin
Rutin
Fidarestat

-12.89
-12.99
-13.31
-14.84
-11.54

Table 2. The hydrogen bond interacting residues of the receptor

PDBID: 1PWM for the lowest binding free energy.
Molecule
Name

Number of
interacting
hydrogen
bonds

The interacting residues

Kaempferol
Myricetin
Fidarestat
Quercetin
Rutin

5
9
3
7
7

TYR48, CYS298, LEU301

TYR48, ASN160, TYR209, CYS298, LEU301
LEU300, SER302
TYR48, ASN160, TYR209, CYS298, LEU301
ALA299, LEU300, SER302

A
Figure 4. Interacting residues with the ligand [Kaempferol (A),
Myricetin (B), Quercetin (C), Rutin (D) and Fidarest (E)] in 3D with
hydrogen bond.

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Figure 5. Two dimensional interactions for ligand [Kaempferol (A),

Myricetin (B), Quercetin (C), Rutin (D) and Fidarest (E)] with interacting residues of the receptor

A
C

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DISCUSSION
Extracts of medicinal plants are known to contain different
chemopreventive or chemotherapeutic compounds, which possess
more than one mechanism of actions. The bioactive components such
as kaempferol, myricetin, quercetin and rutin present in the fruit of
Physalis peruviana L. make this to be considered as a potent source

for the development of novel drugs for the treatment of various diseases 15-18.
Ever since the structure and the pathogenic effects of ALR2 associated with polyol pathway was identified in the lens by Kinoshita
(1965)19 and these works formed the basis for the osmotic stress
hypothesis of sugar cataract formation.

The conversion of glucose to sorbitol catalyzed AR was first identified in 1956 by Hers 5 in the seminal vesicles where glucose is converted to fructose to provide energy source for sperms.
Aldolase reductase inhibitors (ARIs) have been shown to prevent or
slow the progression of DM associated pathologies, such as neuropathy, retinopathy, cataracts and nephropathy both in animal models and human20-22. The majority of the ARIs reported belong to two
classes namely carboxylic acid and spiroimide derivatives.
Figure 6. Surface diagram of the protein with the ligand [Kaempferol
(A), Myricetin (B), Quercetin (C), Rutin (D) and Fidarestat (E)] in
the binding pocket

In the 40 years of ARIs research and after many clinical candidates

only one, epalrestat, is currently commercially for the treatment of

Figure 7. Schematic representation of inhibition of aldose reductase in polyol pathway by Physalis peruviana L. fruit extract.
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diabetic neuropathy, although its use is limited in Japan. In fact,
sorbinil, which was the first extensively tested ARI with good activity
both in vitro and in vivo, was withdrawn from clinical trials because
of hypersensitivity reactions that were related to its hydantoin ring
23,24
.Imirestat, a fluorene analog of sorbinil, also showed appreciable
in vivo activity but was discontinued because of its toxicity 25. Similarly, ARIs such asalreststin 26, epalrestat 8, Zenarestat 27, Zopolrestat
28
and ponalrestat 29 were also discontinued due to their hepatotoxicity.
In the search for new ARIs as potent drug candidates, identifying
inhibitors endowed with good capability to cross biomembranes as
well as devoid of serious unwanted effects is the main challenge for
medicinal chemists. Most of the lead molecules tested so far yields
disappointing results and cellular permeability remains a major hurdle
in the development of ARIs as drugs. Recently, there is growing
interest in the discovery of natural products or plant extracts with
ARI activity 30.
The data obtained through docking studies revealed that the tested
molecules have binding free energy that are almost close to each
other (Table 2), except myricetin, since it gives 9 interacting hydrogen
bonds and hydrophobic interaction from the residues: TRP 219, CYS
298 and LEU 300. A - cation interaction present in the center of an
aromatic ring is closer to 4.5 to a carbon cation [Figure 4 (B), 5(B)].
- interactions shown in the centers of two aromatic rings of
myricetin ligand and protein are closer to 5.0. Further, the stability is
increased by the presence of the two - interaction between the
ligand and the binding site residues TRY 20 and TRY 219 are found to
be the reason for more stability of myricetin. Figure 7 represents the
possible mechanism of action of the major flavonoids present in the
Physalis peruviana L. fruit extract in inhibiting the aldose reductase
in polyol pathway.
CONCLUSION
In conclusion, the present study clearly indicate that the flavonoids
especially myricetin present in the Physalis peruviana fruit extract
mediated the beneficial as well as pharmacological effects at least in
part of alleviating the primary as well as secondary complications of
diabetic mellitus. Studies are in progress to determine the effect of
individual flavonoids present in the fruit extract on the levels of various biochemical and immunological parameters associated with diabetes mellitus.

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ACKNOWLEDGEMENT
The research fellowship (UGC-BSR) of the University Grants Commission (UGC), New Delhi, India, to Mrs. M. Sathyadevi is gratefully
acknowledged.
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UGC, New Delhi, India, Conflict of interest: None Declared

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