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Vol 12, Issue 6, 2019
Online - 2455-3891
Print - 0974-2441
ALOE VERA
IN SILICO
DISALVA X122
1
2
Received: 03 February 2019, Revised and Accepted: 16 April 2019
Obesity is an epidemic disease act as causative for global death. The principal aim of this study is to create an obesity treatment beverage
that is palatable and readily acceptable to the public. Aloe vera juice is one such drink known to assist in reducing obesity. This juice is sold at several
places in Chennai and more easily available for morning walkers along the Marina beach. Although known for its benefits in promoting a slim and fit
physique, its taste is less palatable. The objective of this study is to develop a concoction that will make the A. vera juice tasty without compromising
its nutritive value.
The taste is achieved by the addition of various fruit juices such as orange, lime, sweet lime, muskmelon, and pineapple
with honey and stevia for sweetening. The weight loss ability of the prepared drinks is evaluated using pancreatic lipase inhibitory and the presence
of phytochemicals. To the credit, the present study also determines the efficiency of A. vera compounds for its antiobesity property through in silico
techniques. The significant interaction exhibited by the compounds with the antiobesity target inositol hexakisphosphate kinase 1 (IP6K1) was discussed.
Results: The recipe B containing orange juice: A. vera juice: stevia in the ratio 3:3:1 had good taste and the significant lipase activity. The phytochemicals
present in the A. vera are tannins, flavonoids, alkaloids, steroids, and polyphenols, and these phytochemicals are observed having significant interaction
with protein IP6K1. Aloin A and aloe emodin had significant Glide score and interactions with active site residues.
Natural herbal products for weight reduction may be effective in the treatment of obesity and associated disorders. The potential lipase
inhibition activity of juice may be due to the presence of various phytochemicals such as flavonoids, polyphenol etc. in the Aloe vera.
Obesity, Aloe vera, Weight loss, Aloe vera juice, In silico analysis, Docking studies, Inositol hexakisphosphate kinase 1.
In the present era, obesity is one among the causes for global death and
other diseases. It is an epidemic disease with increased comorbidity
for Type 2 diabetes, coronary heart disease, stroke, fatty liver,
neurodegeneration, cerebrovascular disease, congestive heart failure,
hypertension, lipoprotein abnormalities, and several diseases [1].
Obesity is an abnormal or excessive fat accumulation to the body and
could be explained as a body mass index, kg/m2. More recently, Guthold
et al. [2] published that 28% or 1.4 billion people are physically
inactive which increases the risk for obesity and the development of
non-communicable diseases. Despite physical inactivity, excess intake
of food, especially processed junk foods, endocrine disorders, genes,
medications, and mental disorders also have its role in the cause of
obesity [3,4].
Aloe vera, a common medicinal, readily available, cactus-like plant has
several medicinal applications in treating many ailments. Christaki and
Florou-Paneri [5] reviewed the worth of A. vera under the categories
cosmetic, medicinal, food, and nutrition. This plant being used since
Rigvedic times in India, being reported for its medicinal property
such as treating wounds and burns, protection for skin from X-rays,
lung cancer, intestinal problems, reduces the blood sugar level in
diabetic patients and low-density lipoprotein, increase the high-
density lipoprotein, improves the immune system as well as to fight
the acquired immune deficiency syndrome (AIDS), and allergies [6,7].
A. vera gained its industrial importance and the value for their products
roughly calculated around $125 million and the recent thrust in utilizing
herbal medicines have enlightened its significance in the industrial
development [6]. A report was found that Americans spend 40 billion
dollars on Aloe products as functional foods, drinks, and nutritional
supplements [6]. Aloe juices are widely used as a health drink, soft
drink, laxative drink, sherbet and along with several components such
as lemon juice, electrolyte, soluble fiber, Vitamin B, amino acids and
acetaminophen, other vegetables, yogurts, and cucumber [8]. Due to its
multi-application, the Chinese called the plant as Elixir of youth. The
intake of Aloe preparations as a whole leaf extract and as an inner fillet
gel enhanced the uptake of water/fat-soluble vitamins in the body and
it is the only supplement known for this ability [9]. The applications
of Aloe in health are enormous and scientific records on its antiacid,
antipeptic, gastroprotective, and antiulcer [10].
The emergence of bioinformatics has led the drug discovery and
development process much easier, also cost effective and the existing
high throughput sequencing techniques added its value. In addition, the
juice prepared as a daily dietary ingredient, the present study focuses to
study the potentials of A. vera compounds in interacting the antiobesity
target inositol hexakisphosphate kinase 1 (IP6K1). The target chosen
has significant functionality in regulating cell metabolism and
survival [11]. The recent studies have found that deletion of adipocyte-
specific IP6K1 modulates AMP-activated protein kinase -mediated
adipocyte energy metabolism thereby regulates the fat accumulation in
the body [12]. Secondary metabolites of plants have gained momentum
in the process of drug discovery. Recently, arteether, galantamine,
nitisinone, and tiotropium have been introduced in the US market [13].
Even more, the plant natural compounds were scientifically evaluated
its efficiency against several dreadful diseases such as cancer, HIV/
AIDS, Alzheimer’s, and malaria [14].
© 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2019.v12i6.32380
Research Article
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Asian J Pharm Clin Res, Vol 12, Issue 6, 2019, 331-336
Disalva et al
The beverage preparation consists of three steps which include juice
processing of selected fruits for improving taste, A. vera juice processing
and beverage preparation. The three citrus fruits juices of mosambi,
orange, and lemon as well as the pineapple and muskmelon were chosen
and added with natural sweeteners in the form of powder (stevia and
honey). The A. vera leaves were bought from Pallavaram Market, Chennai.
The juices of each fruit were prepared in the following methods. The
skins of mosambi was removed and roughly blended to extract the juice
and stored immediately since citrus fruits have a tendency to turn to
bitter taste. In the case of orange and lemon, squeezing techniques were
used to obtain the extract and mixed with 3/4th of water. In pineapple and
muskmelon, the skin was removed, and the pulp was diced into pieces
to prepare as juice. The prepared juices were kept aside and/or stored
in the refrigerator until the A. vera leaves were extracted. A. vera leaves
were peeled, diced, and washed several times to remove the stickiness
and pulp was extracted by the blending method and processed into
juice. Furthermore, it was filtered through a strainer and stored in clean
glass jar. As a final step, the beverage was prepared by mixing together
the 30 ml of each fruit juices with 30 ml of A. vera juice separately. The
mixture was blended nicely using cocktail shaker with the addition of
sweeteners. The recipe formulation was tabulated (Table 1).
Phytochemical analysis
The phytochemical analysis was carried out for the food samples
prepared for the presence of tannins, flavonoids, steroids, alkaloids, and
polyphenols [15-17]. The samples were extracted with hydroalcoholic
solvents (70%) (70 ml ethanol and 30 ml of water) for 24 h, and the
filtrates were analyzed for phytochemicals.
Test for tannins
About 1 ml of the sample was boiled in 20 ml of water in a test tube
and then filtered. A few drops of 0.1% ferric chloride was added and
observed for brownish green or a blue-black coloration.
Test for flavonoids
About 5 ml of dilute ammonia solution were added to a portion of the
aqueous filtrate of each plant extract followed by addition of concentrated
H2S04. A yellow coloration observed in each extract indicated the presence
of flavonoids. The yellow coloration disappeared on standing.
Test for steroids
About 2 ml of acetic anhydride was added to 1 ml of an extract of each
sample with 2 ml H2SO4. The color changed from violet to blue or green
in some samples indicate the presence of steroids.
Test for alkaloids
Mayer’s test - to a few (1) ml of the extract, a drop of Mayer’s reagent
was added by the side of the test tube. A creamy or white precipitate
indicates positive.
Test for polyphenols
Ethanol of 4 ml was added to each extract (1 ml) and the resulting
solution was transferred in test tubes and kept warm in a water bath
for 15 min. Three drops of freshly prepared ferric cyanide solution were
added to the extract solution. Formation of a blue-green color indicated
the presence of polyphenols.
The efficiency of weight loss was tested using pancreatic lipase
inhibitory activity. The lipase enzyme was extracted from the pancreas
of chicken (Gallus domesticus).
G. domesticus
The method was followed according to Choi et al. [18]. The pancreas
of freshly slaughtered chicken was collected, washed thoroughly
and placed in ice-cold sucrose solution (0.01 M). The pancreas was
homogenized in 0.01 M sucrose and centrifuged. The supernatant
solution was separated and subjected to ammonium sulfate precipitation
(50% saturation). The obtained white pellets after centrifugation were
dissolved in sucrose solution and again saturated with 50% ammonium
sulfate and centrifuged. Finally, pellets were used as enzyme source by
dissolving in phosphate buffer.
The lipase inhibitory activity was determined using the titration
method [19]. Different concentrations of juice samples were taken in
the concentration of 50, 100, and 150 ml and further mixed with 8 ml of
olive oil, 0.4 ml phosphate buffer, and 1 ml of chicken pancreatic lipase.
The mixture was incubated for 60 min. The reaction was terminated
by the addition of 1.5 ml of a solution containing acetone and 95%
ethanol (1:1). The appearance of pink color from yellow color indicates
the liberated fatty acids, which was determined by titrating the solution
against 0.02 M sodium hydroxide (standardized by 0.01 M oxalic acid)
using phenolphthalein as an indicator and the percentage inhibition of
lipase activity was calculated using the following formula:
= ×
Lipase activity before
treatment
Lipase inhibition percentage 100
Lipase activity after
treatment
In silico
The protein sequence of antiobesity target IP6K1 was retrieved from
UniProt database (Accession ID: Q92551) from the Homo sapiens,
of A. vera
1 A Lemon – 30 30 10
2 B Orange – 30 30 10
3 C Sweet Lime – 30 30 10
4 D Pineapple – 30 30 10
5 E Muskmelon – 30 30 10
A. vera: Aloe vera
1 Lemon with A. vera + ++ + + ++
2 Orange with A. vera + ++ + + ++
3 Sweet lime with A. vera + ++ ++ + ++
4 Pine apple with A. vera + ++ + + ++
5 Muskmelon with A. vera + ++ + + ++
Note: + indicates presence, ++ indicates high concentration, A. vera: Aloe vera
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Asian J Pharm Clin Res, Vol 12, Issue 6, 2019, 331-336
Disalva et al
which contains 441 amino acids and the mass of 50,236 Da. Further,
the retrieved sequence was subjected for alignment using the protein-
protein basic local alignment search tool (BLAST) against the protein
structure database (Protein Data Bank [PDB]), to identify the structure
of similar proteins for protein modeling. The structure prediction
was carried out using the online Tool I-Tasser, and was an automated
structure prediction tools from the structure-based function annotation
(https://zhanglab.ccmb.med. umich.edu/I-TASSER/). The quality of the
modeled structure was studied from the Ramachandran Plot obtained
using the tool, RamPage (http://mordred.bioc.cam.ac.uk/~rapper/
rampage.php). Before the energy of the structure was minimized
using Swiss PDB viewer. The active site pocket for the modeled protein
structure was predicted using SCFbio (http://www.scfbio-iitd.res.
in/dock/ActiveSite.jsp). Plant compounds emodin, anthracene, aloe-
emodin, chrysophanic acid, anthranol, aloin B, aloetic acid, aloin,
aloin A, and the Food and Drug Administration approved drugs for
obesity, orlistat, and phentermine in three dimensional. sdf file format
was retrieved from the PubChem database (https://pubchem.ncbi.nlm.
nih.gov/). Further, the docking studies were carried out using Glide
module of Schrodinger software to analyze the docking score, and
the interactions with specific residues along with the length of bond
formation were visualized in PyMol software.
Functional foods are defined as foods that contain bio-active
ingredients thought to enhance health and fitness. The active
ingredients are phytochemicals, such as lycopene in tomatoes, allicin
in garlic, or isoflavones in soybeans. These phytochemicals, also called
“nutraceuticals,” may be extracted and consumed as supplements, or
may have therapeutic value when consumed in whole food. Majority of
foods, such as whole grains, beans, fruits, vegetables, and herbs contain
phytochemicals of nutraceutical importance. These phytochemicals,
either alone and/or in combination, have tremendous therapeutic
potential in curing various ailments including cancer, diabetic, obesity,
arthritis, ulcer, cardiovascular diseases, and hypertension [20]. Natural
products provide a vast pool of pancreatic lipase inhibitors [21]. A wide
variety of plant products such as saponins, polyphenols, flavonoids,
and caffeine possess lipase inhibitors. Natural products can play a
safe and effective role with obesity especially those containing fibers,
polyphenols, sterols, and alkaloids [22]. In the present study, tannin,
flavonoids, steroids, alkaloid, and polyphenol were present in the
tested sample (Table 2). The presence of these compounds indicates
the positive effect on health.
In the present era, human population faces obesity as the major
problem. However, the number of agents and their products is
utilized for weight loss; perhaps the side effects are the issues to
be concerned. Hence, consistent and safe herbal product for weight
reduction is the urgent need in developing countries. The developed
juice varieties were observed for lipase inhibition and the results are
discussed (Table 3).
Lipase inhibitors may be effectiveness in reducing dietary fat intake
by reducing both the consumption and absorption of fat [23]. Dietary
fat is absorbed by the intestine when it has been subjected to the
action of pancreatic lipases. Pancreatic lipase is a key enzyme in
dietary triacylglycerol absorption, hydrolyzing triacylglycerols to
monoacylglycerols, and fatty acids. Digestion and absorption of dietary
lipids by pancreatic lipase, a major source of excess calorie intake,
can be targeted for the development of weight loss agents. Pancreatic
lipase inhibition is one of the most widely studied mechanisms used
to determine the potential efficacy of natural products as antiobesity
agents. Hence, in the present study, lipase was isolated from the chicken
pancreas and determined the inhibitory activity of pancreatic lipase
when incubated with different concentrations from 50, 100, 150, and
150 ml of Lemon with A. vera, orange with A. vera, sweet lime on with
A. vera, pineapple with A. vera, and muskmelon with A. vera juice. Many
fruits and herbal teas have been extensively studied for the pancreatic
lipase inhibition due to the presence of polyphenols [24,25].
With the increase in the concentration of extracts, the higher inhibition
of the enzyme was observed. The order of lipase inhibition activity
was Lemon with A. vera>Pineapple with A. vera>Muskmelon with
A. vera>Orange with A. vera>Sweet lime on with A. vera. Comparatively
lemon with A. vera juice showed maximum inhibition against enzyme
lipase whereas the lowest inhibition was sweet lime on with A. vera
juice. Thus, an inhibitor of digestive lipase that helps to limit intestinal
fat absorption could be proved as useful medication for the treatment of
hyperlipidemia and holds great promise as a weight loss agent. Among
the various juice, lemon with A. vera juice possesses potential lipase
inhibitors than other juice.
In silico
Protein structure modeling
The protein IP6K1 from H. sapiens contains 441 amino acids, and
the sequence was subjected for BLAST analysis. The hits obtained
have only 32% of similarity against the PDB database; however, for
obtaining a qualified structure, the template should be selected on
the basis of selection rule with the highest sequence similarity [26].
Since in the present analysis, the percentage obtained was 32%,
the multiple template-based structure prediction was performed;
multiple template selection would increase the model accuracy [27].
I-Tasser generated five models, each with a C-score of −2.48, −2.72,
−2.90, −3.95, and −2.74, respectively, whereas the estimated TM-
Score and RMSD were 0.43±0.14 and 13.0±4.2Å, respectively. The
modeled structure was energy minimized using Swiss PDB viewer
of −14389.468 KJ/Mol and the structure is shown in Fig. 1. The active
sites were determined as THR 101, ASP 106, THR 107, THR 108,
GLU 109, ARG 110, GLU 111, GLN 112, PRO 113, ARG 114, ARG 115,
LYS 116, SER 118, ARG 119, ARG 124, SER 125, GLY 126, SER 127,
GLY 18, SER 129, ASP 130, GLU133, GLU134, SER 137, LEU138,
Lemon with A. vera 8.50 7.80 7.20 6.32
Orange with A. vera 9.50 8.60 8.10 7.80
Sweet lime with A. vera 10.20 9.70 8.50 8.10
Pineapple with A. vera 9.20 8.50 7.80 7.10
Muskmelon with A. vera 9.80 8.70 8.20 7.40
A. vera: Aloe vera
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Asian J Pharm Clin Res, Vol 12, Issue 6, 2019, 331-336
Disalva et al
VAL214, PHE217, LYS218, TYR219, PRO220, GLN264, TYR266,
GLN267, ASP269, GLY271, TYR273, GLY341, LYS342, GLU343,
ARG345, GLU347, and SER348.
The absorption, distribution, metabolism, and excretion properties
were determined for the A. vera compounds and drug molecule
orlistat (Table 4). All the compounds analyzed had higher log p value;
however, violation of single Lipinski rule of five is accepted. The
molecules phentermine, antracene, anthranol had a less molecular
weight <200, emodin, aloe-emodin, and chrysophanic acid had in the
range of 200–300, whereas orlistat, aloin B, aloetic acid, and aloin A
had >400. Donor and acceptor hydrogen bond are most important
since those are involved in the formation of significant interaction
between the compound and the protein. The compound anthracene
had no ability to donate as well as to accept the hydrogen bonds. The
surface area solvent accessible is important criteria which reveal the
polar interaction and the solubility of the compounds in the water
environment. The compounds studied in the present research indicated
significant solvent accessibility of surface area value. The table also
shows the blood/blood partition coefficient for the compounds which
ranges between the −3.0 and 1.2 and the human oral absorption was
determined to predict the ability of the compounds for oral intake. The
drug orlistat had a low level of oral absorption whereas the compounds
emodin, phentermine, aloe-emodin, chrysophanic acid, and anthranol
had significantly high for oral absorption.
The docking studies for the compounds and drug orlistat with
the protein IP6K1 1 were determined using the software Glide, a
Schrodinger suite. The Glide score (G. Score), interacting residues, bond
length, and number of hydrogen bonds were tabulated (Table 5). The
plant compounds had significant G. score value that the drug orlistat
where the G. score was observed to be −2.89 Kcal/mol. Among the plant
compounds, aloin A had significant G. score of −7.46 Kcal/mol followed
by aloin B and aloe emodin of −7.41 and −7.35 Kcal/mol, respectively.
The respective G. score of aloetic acid, emodin, and chrysophanic
acid is −6.63, −6.33, and −6.22 Kcal/mol. The compounds anthranol
and phentermine had G. score in the range of −4 and anthracene had
−3.95 Kcal/mol. The interactions were higher to lower in the order
of aloetic acid>aloe emodin>emodin>aloin A, chrysophanic acid,
orlistat>aloin B>anthranol, phentermine.
The interactions with active sites include GLN 112, ARG 115, ARG 119,
ARG 124, ASP 130, PHE 217, LYS 218, and TYR 266. Perhaps, apart
A. vera
Donor
SASA
Human Oral
Orlistat (3034010) 495.741 0.25 7.75 21.148 961.847 −2.678 1
Emodin (3220) 270.241 1 4.25 12.607 479.225 −1.541 3
Phentermine (4771) 149.235 2 1 8.782 383.538 0.487 3
Anthracene (8418) 178.233 0 0 7.45 404.551 0.192 1
Aloe-emodin (10207) 270.241 1 5.2 12.997 478.805 −1.594 3
Chrysophanic acid (10208) 254.242 0 3.5 10.583 466.991 −0.987 3
Anthranol (10731) 194.232 1 0.75 9.357 411.593 0.193 3
Aloin B (14989) 418.399 5 11.7 26.431 626.291 −2.823 1
Aloetic acid (5464178) 450.231 1 9.2 18.705 597.175 −4.481 1
Aloin A (12305761) 418.399 5 11.7 26.634 641.8 −3.064 1
HB: Hydrogen bond, QPlogPo/w: Octanol/water coefficient, SASA: Solvent accessibility of surface area, QPlogBB: Blood-brain barrier, A. vera: Aloe vera
A. vera
Name
Aloin A
(12305761)
−7.46 Lys218 (H-O)
Lys218 (H-O)
Arg115 (H-O)
Gln112 (H-O)
Gln112 (O-H)
2.2
1.7
2.7
2.4
2.2
5
Aloin B
(14989)
−7.41 His272 (N-H)
Arg115 (H-O)
2.0
2.1
2
Aloe-Emodin
(10207)
−7.35 Arg22 (O-H)
Lys189 (O-H)
Arg124 (H-O)
Arg124 (H-O)
Arg119 (H-O)
Arg119 (H-O)
Asp43 (O-H)
2.1
1.8
2.1
2.1
1.9
2.0
1.6
7
Aloetic acid
(5464178)
−6.63 Arg41 (H-O)
Arg41 (H-O)
Arg119 (H-O)
Arg119 (H-O)
Arg124 (H-O)
Asp130 (O-H)
Arg115 (H-O)
Lys189 (O-H)
2.6
2.6
2.3
1.9
1.9
2.0
2.1
1.8
8
Emodin
(3220)
−6.33 Lys189 (O-H)
Lys132 (H-O)
Asp130 (O-H)
Arg124 (H-O)
Arg124 (H-O)
Arg22 (O-H)
1.8
2.6
1.9
2.1
2.2
2.0
6
Chrysophanic
acid (10208)
−6.22 Lys218 (O-H)
Lys218 (O-O)
Gln112 (H-O)
Arg114 (H-O)
Phe217 (O-HH)
2.1
2.9
2.7
2.7
1.8
5
Anthranol
(10731)
−4.91 Lys218 (O-H) 1.9 1
Phentermine
(4771)
−4.33 Asp43 (O-H) 1.6 1
Anthracene
(8418)
−3.95 NIL NIL NIL
Orlistat
(3034010)
−2.89 Tyr266 (H-O)
Lys218 (O-H)
2.7
2.2
2
IP6K1: Inositol hexakisphosphate kinase 1
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Disalva et al
from active sites, the following are the residues had interactions with
the plant compounds and orlistat, ARG22, ARG 41, ASP 43, ARG 114,
LYS 132, and LYS 189. The interactions of each compound with the
protein IP6K1 are shown in Table 6. The compound anthracene had
no interactions as it has no hydrogen donor and hydrogen acceptor
property as predicted in the ADME analysis.
The in silico studies indicated the efficiency of A. vera compounds in
interacting with the target protein IP6K1 and the ADME properties also
indicated its human oral absorption property. The plant is reported in
cleansing the digestive system and encourages in relaxing constipation
as well as increases the energy levels to maintain a healthy body
weight [28].
Emodin versus IP6K1 Phentermine versus IP6K1
Aloe-Emodin versus IP6K1 Chrysophanic acid versus IP6K1
Anthranol versus IP6K1 Aloin B versus IP6K1
Aloetic acid versus IP6K1 Aloin A versus IP6K1
Orlistat versus IP6K1
IP6K1: Inositol hexakisphosphate kinase 1
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Asian J Pharm Clin Res, Vol 12, Issue 6, 2019, 331-336
Disalva et al
Obesity is characterized as abnormal or excessive fat deposition in
adipose tissue and other internal organs such as liver, heart, and skeletal
muscle. It is a chronic disorder of carbohydrate and fat metabolism and
poses a risk to the health and well-being of humans. Consistent and safe
herbal product for weight reduction is a need in developing countries.
Natural herbal products for weight reduction may be effective in the
treatment of obesity and associated disorders. The potential lipase
inhibition activity of juice may be due to the presence of various
phytochemicals such as flavonoids, polyphenol etc. in the Aloe vera.
The author declares that this work was done by the author named in
this article.
No conflicts of interest are associated with this work.
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