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Accepted Manuscript
GC-MS and molecular docking studies of Hunteria umbellata methanolic extract as a
potent anti-diabetic
Olusola Abiola Ladokun, Aminu Abiola, Durosinlorun Okikiola, Famuti Ayodeji
PII:
S2352-9148(17)30251-4
DOI:
10.1016/j.imu.2018.08.001
Reference:
IMU 128
To appear in:
Informatics in Medicine Unlocked
Received Date: 23 December 2017
Revised Date:
24 July 2018
Accepted Date: 12 August 2018
Please cite this article as: Ladokun OA, Abiola A, Okikiola D, Ayodeji F, GC-MS and molecular docking
studies of Hunteria umbellata methanolic extract as a potent anti-diabetic, Informatics in Medicine
Unlocked (2018), doi: 10.1016/j.imu.2018.08.001.
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*Corresponding Author, olusola.ladokun@lcu.edu.ng
* Corresponding Author:
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Prof. Olusola Abiola Ladokun
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GC-MS and molecular docking studies of Hunteria
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umbellata methanolic extract as a potent anti-diabetic.
Department of Biochemistry
Ibadan, Oyo State, Nigeria
e-mail: olusola.ladokun@lcu.edu.ng
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TEL: +2348034995499
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Lead City university
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Abstract
Background: The purpose of this study was to investigate the diabetic effect of phytocompounds
synthesized from Hunteria umbellata using GC-MS analysis and molecular docking studies.
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Objective: Peroxisome proliferator-activated receptor gamma (PPAR-?) agonists are beneficial in
the treatment of diabetes by stimulating insulin sensitivity and antagonizing hepatic
gluconeogenesis. The aim of the present study was to investigate the PPAR-? agonist property of
phytocompounds from Hunteria umbellata using an in-silico approach.
Methods: Molecular docking of Hunteria umbellata on human PPAR-? protein was determined by
Auto/Vina in Pymol 4.2 and compared with Gilbenclamide, a known agonist of PPAR-?.
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Results: Our present study reports the phytochemical analysis of the extracts of the seeds and
leaves of Hunteria umbellata. 21 compounds were revealed through GC-MS analysis and screened
using AutoDock/Vina against PPAR-?. Docking studies recommended that 2,2-Benzylidenebis (3methylbenzofuran) an existing phytochemical from the seed of Hunteria umbellata had the highest
fitness score of -11.3 Kcal/mol and hence could be a potent antidiabetic drug.
Conclusions: Hunteria umbellata seed extract and its compound 2,2-Benzylidenebis (3methylbenzofuran) have a significant antidiabetic activity against PPAR-?. The molecular binding
interaction of an in-silico data demonstrated that 2,2-Benzylidenebis (3-methylbenzofuran) has
more specificity towards the PPAR-? binding site and could be a potent antidiabetic compound.
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Keywords: Diabetes mellitus, Hunteria umbellata, 2,2-Benzylidenebis(3-methylbenzofuran),
Docking, Gas Chromatography-Mass Spectrometry (GC-MS), peroxisome proliferator-activated
receptor gamma.
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1. Introduction
Diabetes mellitus (DM) is recognized as a metabolic disorder which results from the defect in
insulin secretion and action [1]. According to World Health Organization, an estimated 422 million
adults are living with diabetes mellitus (WHO 2016) [2]. In 2013, 381 million persons have been
shown to have diabetes according to the International Diabetes Federation (?Simple treatment to
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curb diabetes?) [3] and the number is projected to double by 2030.
Several research studies have identified peroxisome proliferator-activated receptor as key regulators
of glucose and lipid metabolism [4, 5], because they act as transcription factors activating protein
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synthesis in a wide variety of processes. Peroxisome proliferator-activated receptor gamma
upregulates expression of adipocyte glycerol kinase which therefore stimulates glycerol
incorporation into triglyceride. Glucose disposal in the peripheral tissue has been shown to be
glucose transporter 1 and 4 [6, 7].
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augmented by PPAR-y which therefore increases the expression of the glucose transporter gene
Gilbenclamide is a second-generation sulfonylurea that reduces blood glucose by increasing insulin
secretion from pancreatic beta cell [8]; this helps to reduce the amount of sugar in the blood.
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Gilbenclamide drugs produce several side effects, such as nausea, vomiting, constipation, diarrhoea
and low blood sugar. There is a need to search for a new peroxisome proliferator- activated receptor
gamma agonist with little or no side effect.
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Hunteria umbellata (HU) (Apocynaceae) is a small tree of about 15-22 m in height with a dense
evergreen crown [9]. The leaves have been described as broad, abruptly acuminate and broadly
lineate [10, 11]. The fruit is about 5-25 cm in diameter and consists of two separate globose
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mericaps 3-6 cm long, yellow and smooth. 8-25 seeds embedded in a gelatinous pulp [10]. Hunteria
umbellata have been shown to be used in traditional herbal medicine in the treatment of different
ailment such as peptic ulcers, piles, yaws, dysmenorrhea, fever, infertility [12], helminthic infection
[13], bacterial infection [14] and Diabetes [15]. Recent research has shown that Hunteria umbellata
can be used to reduce glucose level in the blood [15, 16], but little has been done to show and
validate the constituent in this plant that acts as a potent antidiabetic agent.
The aim of this research is to investigate the antidiabetic constituents present in the leaf and seed of
Hunteria umbellata using GC-MS analysis and molecular docking studies to determine the potent
compound which can be used in the treatment of diabetics.
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2. Materials and methods
2.1.
Collection of plant materials
Hunteria umbellata seeds and leaves were purchased from Bode market, Molete Ibadan,
Oyo state, Nigeria.
2.2.
Preparation of the extract
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The mature fresh leaves and seeds of Hunteria umbellata were washed separately in fresh
water thoroughly 2-3 times and once finally with sterile water to remove adhering dust. The leaves
and seeds were dried on sterile blotter under shade and then powdered in a mixture grinder. About
2g of the plant leaves and seeds extract was weighed separately into tumble and placed inside
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soxhlet extractor. A mixture of n-hexane and methanol (50/50) v/v was placed within a roundbottom flask. The flask was attached to the main soxhlet extractor and the condenser was attached
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to the extractor, which was connected to a pipe where there was continuous flow of water. The
extractor was heated using a heating chamber for about 2-3hrs. The solvent was run through the
tumble containing the sample, and this trapped all the possible extract into the solvent inside the
round bottom flask, and the extract was then cleaned by passing it through a column packed with
silica gel that had already been saturated with methanol. The extract was dried using a hydrous
sodium sulphate.
The cleaned extract was then concentrated to about 1ml using nitrogen
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concentration before being introduced into the GC-MS analyser.
Gas Chromatography-Mass Spectrometry (GC-MS) Analysis
The gas chromatography ? mass spectrometry (GC-MS) analysis of the leaves and seeds
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Hunteria umbellata was performed using a GC-MS (Modal; Agilent technologies 7890A) equipped
with a VF ? 5ms fused silica capillary column of 30m length, 0.25mm diameter and 0.25mm film
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thickness. For GC-MS detection, an electron ionization system with ionization energy of 70eV was
used. Helium gas (99.99%) was used as a carrier gas at a constant flow rate of 1ml/min. Injection
and mass transfer line temperature were set at 200 and 2400C respectively. The oven temperature
was programmed from 800C to hold for 2mins@ 100C /min to 2400C to hold for 6mins. 2ml of
water solution of the samples was manually inserted in the split less mode, with a split ratio of 1:40
and with a mass scan of 50-600amu. The total running time of the GC-MS was 35min. The relative
percentage of each extract constituent was expressed as a percentage with peak area normalization.
Interpretation of the mass spectrum of the plant extracts was conducted using the database of the
National Institute of Standard and Technology (NIST) library, having more than 62,000 spectral
patterns. The spectra of the compounds were compared with the spectra of the National Institute of
Standard and Technology (NIST) library database (figure 1&2).
2.4.
Molecular Docking
Molecular Docking is theACCEPTED
process by which
two molecules fit together in 3D space; it is a
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key tool in structural biology and computer-aided drug design [17]. AutoDock vina 4.0 [18] was
used to carry out the molecular docking. The AutoDock tool was used to calculate the ligand
binding to PPAR gamma model using a grid spacing of 0.375 angstroms and the grid points in X, Y
and Z axis were set at 60��. The grid center coordinates was placed at X: 19.92, Y: 7.12, Z:
15.48. The grid boxes were placed at the binding site of the enzyme, which gives sufficient space
the binding energy and the interaction of the docked structure.
2.5.
Protein Preparation
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for the ligand rotation and translation. The results obtained from AutoDock were analysed to study
The 3D structure of PPAR gamma (PDB ID: 4EM9) was downloaded from the Protein Data
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Bank(PDB) (http://www.pdb.org/pdb/home/home.do) before initiating the docking simulations. All
non-protein molecules were removed from 4EM9; for any alternative atom locations, only the first
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location was retained. All the docking calculations were performed using AutoDock 4.0. PPAR
gamma was modified by adding polar hydrogen and then kept rigid in the docking process, whereas
all the torsional bonds of ligands were set free by the Ligand module in AutoDock Tools.
2.6.
Ligand Preparation
The 2D structure of the ligand isolated from the seeds and leaves of the plants was drawn
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using the ChemAxon software called MarvinSketch (https://www.chemaxon.com/). To prepare the
ligand for docking, it was then converted to a 3-Dimentional structure with a force field of
MMFF94.
Docking confirmation using Mcule
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2.7.
Mcule accelerates early-phase drug discovery by its integrated molecular modelling tools,
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computational capacity and high-quality compound database (https://mcule.com/dashboard/).
Molecular docking using Mcule was done in the Structure-based virtual screen - Workflow builder.
The ligand was uploaded in 2D. The protein which is the target was uploaded in 3D with a binding
site centre X: 19.92, Y: 7.12, Z: 15.48. The simulation was RUN with a maximum hit of 1000.
2.8. Pchembl Calculation
Pchembl Calculation was done using Chembl (https://www.ebi.ac.uk/chembl/). The target
fasta file was copied from pdb (http://www.rcsb.org/pdb/explore/explore.do?structureId=4EM9)
and uploaded at the Protein target BLAST search in Chembl. The target associated Bioactivities
with Target ID of CHEMBL235 was downloaded. To calculate the Pchembl, the target associated
Bioactivities was docked against PPAR gamma with a config.txt parameter (Table 3). After
docking, the results were harvested by 'egrep'. The Coefficient was determined by plotting a graph
shown in (figure 9), of the docked score against the Pchembl value (agonist).
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3. Results and Discussion
The characterization of the methanol fractions of the leaves and seeds of Hunteria umbellata
were carried out by GC-MS which revealed the presence of 21 phytochemicals as shown in (Figure
2&3). To investigate the detailed intermolecular interactions between the ligand and the target
protein (PPAR-?), an automated docking program AutoDock vina 4.2 was used. It performs gridbased ligand docking with energetics and searches for favorable interactions between one or more
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typically small ligand molecules and a typically larger receptor molecule, usually a protein. Three
dimensional structural information on the target was taken from the Protein Data Bank (PDB) entry
4EM9. The receptor preparation was done to delete water molecules not associated with active sites
and also to regenerate the native status, and also for the addition of hydrogen atoms. The
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compounds extracted from Hunteria umbellata obtained from GC-MS analysis were docked into
the active site of PPAR-?. A correlation was calculated by Glide score. The most accurate method
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of evaluating the accuracy of a docking procedure is to determine how closely the lowest energy
pose (binding conformation) is predicted by the object scoring function. Three parameters are
usually considered when calculating results. These are, G-score, H-bond energy and residual
interaction. This forms the basis whereby the binding affinity of ligand towards the binding receptor
is discussed. The more negative the value of the standard free energy charge, the better the binding
affinity of the ligand with receptor. Residual interaction shows where the ligand exactly binds to a
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particular amino acid of the protein [19].
The phytochemicals obtained from the leaves and seeds were analysed by comparing their
binding affinity to the receptor. According to the graph in Fig. 8, 2,2'-Benzylidenebis(3methylbenzofuran) from Hunteria umbellata seed shows a high binding affinity of -11.3 Kcal/Mol
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as predicted by AutoDock/Vina. The result was confirmed by using Mcule which is an online drug
discovery platform. The mcule ID C-354746429 gives a docking result of -11.5 Kcal/Mol, which
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therefore validates the docked result of AutoDock/Vina. From this result 2,2'-Benzylidenebis(3methylbenzofuran) from Hunteria umbellata seed is identified as the lead compound and thereby
acts as a potent antidiabetic target.
In order to confirm the potency of the lead compound from the seed with a standard drug,
Glibenclamide was docked with PPAR-? using AutoDock/Vina. This gives a binding result of 10.7 Kcal/mol with the binding pose as shown in Fig.7.
Docking analysis of 4EM9 with 2,2'-Benzylidenebis(3-methylbenzofuran) enabled us to
identify specific amino acid residues viz. SER6 ALA7 ASP8 LEU9 ARG10 ALA11 LEU12
ALA13 LYS14 HIS15 LEU16 ASP18 SER19 TYR20 ILE21 LYS22 SER23 PRO25 THR27
LYS28 ALA29 LYS30 ALA31 ARG32 ALA33 ILE34 LEU35 THR36 GLY37 LYS38 THR39
THR40 ASP41 LYS42 SER43 PRO44 PHE45 VAL46 ILE47 TYR48 ASP49 MET50 ASN51
SER52 LEU53 MET54 MET55 GLY56 GLU57 ASP58 LYS59 ILE60 LYS61 PHE62 LYS63
HIS64 ILE65 THR66 PRO67 LEU68 GLN69 GLU70 GLN71 SER72 LYS73 GLU74 VAL75
ALA76 ILE77 ARG78 ILE79 PHE80 GLN81 GLY82 CYS83 GLN84 PHE85 ARG86 SER87
VAL88 GLU89 ALA90 VAL91 GLN92 GLU93 ILE94 THR95 GLU96 TYR97 ALA98 LYS99
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SER100 ILE101 PRO102 GLY103
PHE104 VAL105 ASN106 LEU107 ASP108 LEU109
ASN110 ASP111 GLN112 VAL113 THR114 LEU115 LEU116 LYS117 TYR118 GLY119
VAL120 HIS121 GLU122 ILE123 ILE124 TYR125 THR126 MET127 LEU128 ALA129 SER130
LEU131 MET132 ASN133 LYS134 ASP135 GLY136 VAL137 LEU138 LE139 SER140 GLU141
GLY142 GLN143 GLY144 PHE145 MET146 THR147 ARG148 GLU149 PHE150 LEU151
LYS152 SER153 LEU154 ARG155 LYS156 PRO157 PHE158 GLY159 ASP160 PHE161
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MET162 GLU163 PRO164 LYS165 PHE166 GLU167 PHE168 ALA169 VAL170 LYS171
PHE172 ASN173 ALA174 LEU175 GLU176 LEU177 ASP178 ASP179 SER180 ASP181
LEU182 ALA183 ILE184 PHE185 ILE186 ALA187 VAL188 ILE189 ILE190 LEU191 SER192
GLY193 ASP194 ARG195 PRO196 GLY197 LEU198 LEU199 ASN200 VAL201 LYS202
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PRO203 ILE204 GLU205 ASP206 ILE207 GLN208 ASP209 ASN210 LEU211 LEU212 GLN213
ALA214 LEU215 GLU216 LEU217 GLN218 LEU219 LYS220 LEU221 ASN222 HIS223
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PRO224 GLU225 SER226 SER227 GLN228 LEU229 PHE230 ALA231 LYS232 LEU233
LEU234 GLN235 LYS236 MET237 THR238 ASP239 LEU240 ARG241 GLN242 ILE243
VAL244 THR245 GLU246 HIS247 VAL248 GLN249 LEU250 LEU251 GLN252 VAL253
ILE254 LYS255 LYS256 THR257 GLU258 THR259 ASP260 MET261 SER262 LEU263 HIS264
PRO265 LEU266 LEU267 GLN268 GLU269 ILE270 TYR271 LYS272 ASP273 LEU274 and
TYR275 within and around the 4EM9 binding pocket, which plays an important role in the ligand
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binding affinity as shown in Fig. 5. The docking of 4EM9 and 2,2'-Benzylidenebis(3methylbenzofuran) is shown in Fig. 6. Our in-silico experiments demonstrate that 2,2'Benzylidenebis(3-methylbenzofuran) from the seed of Hunteria umbellata binds 4EM9, and in
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itself activates its function and thus may act as an anti-diabetic drug.
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Abundance
TIC: sample Sb.D\data.ms
22.352
1.3e+07
1.2e+07
1.1e+07
1e+07
9000000
7000000
6000000
5000000
9.072
16.132
4000000
3000000
16.334
22.99
20
4.237
23.826
14.394
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8.601
2000000
23.1
23
49
.050
1000000
16.068
8.463
6.00
20.851
27.293
26.855
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
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4.00
13.588
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8000000
Time-->
Figure 1. GC-MS chromatogram of methanolic extract of the seed of Hunteria umbellata
Abundance
TIC: sam
ple Sb.D\ data.m
s
22.352
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1.3e+07
1.2e+07
1.1e+07
1e+07
9000000
7000000
6000000
5000000
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8000000
9.072
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4000000
16.132
3000000
8.601
2000000
16.334
23.1
23
49
.050
1000000
8.463
4.00
6.00
8.00
22.99
20
4.237
23.826
14.394
16.068
13.588
27.293
26.855
20.851
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00
Tim
e-->
Figure 2. GC-MS chromatogram of methanolic extract of the leaves of Hunteria umbellata
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2.
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1.
Benzenemethanol
4.
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3.
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2,2'-Benzylidenebis(3-methylbenzofuran)
Phenol, 6-methoxy-2-[2-(2-quinolyl)ethenyl
6.
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5.
Glibenclamide
2-Ethylacridine
5-Methyl-2-phenylindolizine
7.
Urs-12-en-24-oic acid
11-Octadecenoic acid
8.
9-Octadecenoic acid (Z)-
Figure 3. 2-Dimentional structure of the compound isolated from the seed of Hunteria umbellata
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10.
8,11-Octadecadienoic acid
11.
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12.
Quinolin-2(1H)-one
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Caffeine
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13.
2-Methoxyresorcinol
Fig. 3. (continued)
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2-Methoxyresorcinol
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9.
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2.
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1.
1-Methyl-3-phenylindole
3.
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4.
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1,2-Benzisothiazol-3-amine
1,4-Eicosadiene
11-Octadecenoic acid
6.
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5.
Dodecanoic acid
7.
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Glibenclamide
10,13-Octadecadienoic acid
Methyl stearate
8.
Hexadecanoic acid
Figure 4. 2-Dimentional structure of the compound isolated from the leaves of Hunteria umbellata
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Table 1. Binding analysis of phytochemicals isolated from the seed of Hunteria umbellata with PPAR gamma
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1.
2,2'-Benzylidenebis(3-methylbenzofuran)
-11.3
2.
2-Ethylacridine
-9.8
3.
2-Methoxyresorcinol
-5.3
4.
5-Methyl-2-phenylindolizine
-9.1
5.
6-Methoxy-9H-purine
-5.3
6.
8,11-Octadecadienoic acid
-6.7
7.
9-Octadecenoic acid (Z)
-6.2
8.
11-Octadecenoic acid
-6.3
9.
Caffeine
-6.4
10.
Benzenemethanol
-5.7
11.
Hexadecanoic acid
-6.1
12.
Quinolin-2(1H)-one
13.
Urs-12-en-24-oic acid
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COMPOUNDS
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AFFINITY (kcal/mol)
S/N
-7.0
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-7.4
Table 2. Binding analysis of phytochemical isolated from the leave of Hunteria umbellata with PPAR gamma
S/N
COMPOUNDS
AFFINITY (kcal/mol)
1.
1,2-Benzisothiazol-3-amine
2.
1,4-Eicosadiene
3.
1-Methyl-3-phenylindole
-8.9
4.
10,13-Octadecadienoic acid
-6.4
5.
11-Octadecenoic acid
-6.3
6.
Dodecanoic acid
-6.5
7.
Hexadecanoic acid
-7.4
8.
Methyl stearate
-6.0
-6.1
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-6.5
Table 3. Config.txt for Chembl molecular docking using Auto/Vina
center_x
center_y
19.92
7.12
center_z
15.48
size_x
22.50
size_y
22.50
size_z
22.50
num_modes
1
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Figure 5. Interaction and superimposed structure of compound of 2,2'-Benzylidenebis(3-methylbenzofuran) with PPAR
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gamma amino acid residue
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Figure 6. Interaction and superimposed structure of compound of 2,2'-Benzylidenebis(3-methylbenzofuran)
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with PPAR gamma
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2
0
-2
Y- axis
3
4
5
6
7
8
9
10
11
12
13
SEED
LEAVE
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Figure 7. Interaction and superimposed structure of compound of Glibenclamide with PPAR gamma
-6
-8
-10
-12
X- axis
Figure 8. Graphical presentation of the binding affinity between the plant and seed of Hunteria umbellata
0
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1
2
3
4
5
6
7
8
9
10
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-2
-4
Docking
-6
Linear (Docki
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-8
y = -0.3083x - 6.8429
R� = 0.4376
-10
-12
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Figure 9. Coefficient of determination (R2 ) Pchembl value of PPAR-?
4.0 Conclusions
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The receptor (Protein) and ligand plays an important role in structural based drug design. In the
present work, phytochemicals were obtained from the leaf and the seed of Hunteria umbellata by
Gas Chromatography Mass spectrometry (GC- MS) analysis. The presence of different bioactive
compounds provides evidence for the efficacious use of plant parts for various ailments by
traditional specialists. In this study, we docked the receptor PPAR? with the phytochemicals and
from this, 2,2'-Benzylidenebis(3-methylbenzofuran) from the plant seed holds a promising lead
target formation against diabetes based on molecular docking analysis (minimum hydrogen bond
length and maximum docked score). In-vivo and in-vitro approaches are therefore recommended to
elucidate the molecular mechanism of this compound to act as potent drug against type 2 diabetes.
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[19] Himaja M., Abdulla Md,et al. ?Synthesis, Docking studies and anti-oxidant activity of tetra
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peptide FGVY? International Journal of Research in Ayurveda andPharmacy,2011,2(3): 905- 910.
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Ethical Statement
I testify on behalf of all co-authors that our article submitted to Informatics in Medicine:
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Title: GC-MS and molecular docking studies of Hunteria umbellata methanolic extract as
a potent anti-diabetic.
All authors:
Lead city University
Lead city University
Lead city University
Honey T Scientific
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1. Olusola Ladokun
2. Aminu Abiola
3. Durosinlorun Okikiola
4. Famuti Ayodeji
Date: 3/08/2018
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1) this material has not been published in whole or in part elsewhere;
2) the manuscript is not currently being considered for publication in another
journal;
3) all authors have been personally and actively involved in substantive work
leading to the manuscript, and will hold themselves jointly and individually
responsible for its content.
Corresponding author?s signature:
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*Corresponding Author, olusola.ladokun@lcu.edu.ng
* Corresponding Author:
Prof. Olusola Abiola Ladokun
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Department of Biochemistry
Lead City universityGC-MS and molecular docking studies of Hunteria
umbellata methanolic extract as a potent anti-diabetic.
Ibadan, Oyo State, Nigeria
e-mail: olusola.ladokun@lcu.edu.ng
TEL: +2348034995499
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