Phytochemical Composition Anti-Microbial Anti-Oxidant and Anti-Diabetic Effects of Solanum Elaeagnifolium Cav. Leaves in Vitro and in Silico Assess

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/tbsd20
Phytochemical composition, anti-microbial, anti-

oxidant and anti-diabetic effects of Solanum
elaeagnifolium Cav. leaves: in vitro and in silico
assessments
Francis Xavier T., Sabitha R., Freeda Rose A. K., Balavivekananthan S.,
Kariyat R., Ayyanar M., Vijayakumar S., Prabhu S., Amalraj S., Shine K. &
Thiruvengadam M.
To cite this article: Francis Xavier T., Sabitha R., Freeda Rose A. K., Balavivekananthan S.,
Kariyat R., Ayyanar M., Vijayakumar S., Prabhu S., Amalraj S., Shine K. & Thiruvengadam M. (05
Jan 2024): Phytochemical composition, anti-microbial, anti-oxidant and anti-diabetic effects of
Solanum elaeagnifolium Cav. leaves: in vitro and in silico assessments, Journal of Biomolecular
Structure and Dynamics, DOI: 10.1080/07391102.2023.2300124
To link to this article: https://doi.org/10.1080/07391102.2023.2300124
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2023.2300124
Phytochemical composition, anti-microbial, anti-oxidant and anti-diabetic effects

of Solanum elaeagnifolium Cav. leaves: in vitro and in silico assessments
Francis Xavier T.a, Sabitha R.a, Freeda Rose A. K.b, Balavivekananthan S.a�, Kariyat R.c, Ayyanar M.d,
Vijayakumar S.d, Prabhu S.e, Amalraj S.e, Shine K.f and Thiruvengadam M.g
a
Ethnopharmacological Research Unit, PG and Research Department of Botany, St. Joseph’s College (Autonomous), Bharathidasan
University, Tiruchirappalli, Tamil Nadu, India; bPG and Research Department of Botany, Holy Cross College (Autonomous), Bharathidasan
University, Tiruchirappalli, Tamil Nadu, India; cDepartment of Biology, The University of Texas, Rio Grande Valley, W University Dr, Edinburg,
TX, USA; dPG and Research Department of Botany, A.V.V.M. Sri Pushpam College (Autonomous), Bharathidasan University, Poondi, Tamil
Nadu, India; eDivision of Phytochemistry and Drug Design, Department of Biosciences, Rajagiri College of Social Sciences, Cochin, Kerala,
India; fDepartment of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia; gDepartment of Crop
Science, College of Sanghuh Life Science, Konkuk University, Seoul, Korea
Communicated by Ramaswamy H. Sarma
ABSTRACT ARTICLE HISTORY

The aim of this study was to screen the chemical components of Solanum elaeagnifolium leaves and Received 9 June 2023
assess their therapeutic attributes with regard to their antioxidant, antibacterial, and antidiabetic activ Accepted 20 December 2023
ities. The antidiabetic effects were explored to determine the a-amylase and a-glucosidase inhibitory
KEYWORDS
potential of the leaf extract. To identify the active antidiabetic drugs from the extracts, the GC-MS-
Antidiabetic; antioxidant;
screened molecules were docked with diabetes-related proteins using the glide module in the bacteriostatic; molecular
Schrodinger Tool. In addition, molecular dynamics (MD) simulations were performed for 100 ns to docking; secondary
evaluate the binding stability of the docked complex using the Desmond module. The ethyl acetate metabolites; Solanum
had a significant total phenolic content (TPC), with a value of 79.04 ± 0.98 mg/g GAE. The ethanol elaeagnifolium
extract was tested for its minimum inhibitory concentration (MIC) for its bacteriostatic properties. It
suppressed the growth of B. subtilis, E. coli, P. vulgaris, R. equi and S. epidermis at a dosage of
118.75 mg/mL. Moreover, the IC50 values of the ethanol extract were determined to be 17.78 ± 2.38 in
the a-amylase and and 27.90 ± 5.02 mg/mL in a-glucosidase. The in-silico investigation revealed that
cyclolaudenol achieved docking scores of −7.94 kcal/mol for a-amylase. Likewise, the a-tocopherol
achieved the docking scores of −7.41 kcal/mol for glycogen phosphorylase B and −7.21 kcal/mol for
phosphorylase kinase. In the MD simulations, the cyclolaudenol and a-tocopherol complexes exhibited
consistently stable affinities with diabetic proteins throughout the trajectory. Based on these findings,
we conclude that this plant could be a good source for the development of novel antioxidant, anti
bacterial, and antidiabetic agents.
CONTACT Prabhu S [email protected] Division of Phytochemistry and Drug Design, Department of Biosciences, Rajagiri College of Social
Sciences, Cochin 683 104, Kerala, India.
�Department of Biochemistry, Rev. Jacob Memorial Christian College, Ambilikkai, Dindigul, Tamil Nadu, India-624 612.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2023.2300124.
� 2024 Informa UK Limited, trading as Taylor & Francis Group
2 F. X. T. ET AL.
1. Introduction therapeutics against cancer, diabetes, the central nervous

system, and some communicable diseases caused by patho
Since ancient times, plants have been used by people world genic microorganisms (Rizvi et al., 2022).
wide for various purposes, including food, medicine, feed, Solanum species are known for their high content of ster
and building materials (Cordero et al., 2023; Prabhu et al., oidal alkaloids, particularly solasodine, which is the most
2022; Torres-Leo �n et al., 2023). In Asian countries, plants are
abundant in the berries of Solanum elaeagnifolium (Balah &
used as medicines for communicable and non-communicable AbdelRazek, 2020). Solanum elaeagnifolium belongs to the
diseases in a number of traditional medicinal systems such nightshade family (Solanaceae), native to the USA, Mexico,
as Ayurveda, Unani, Kampo, and traditional Chinese medicine and South Africa, and is widely distributed in some European
(Sureshkumar et al., 2021). For more than three decades, regions and many countries in Asia, Africa, and Australia
numerous studies have documented that plant extracts con (Roberts & Florentine, 2022). In addition to vegetative repro
tain a variety of polyphenol molecules, including flavonoids, duction by rhizomes and root fragments, sexual reproduction
anthocyanins, and tannins, which have been shown to have generally occurs in the seeds. Because the seeds and leaves
powerful antioxidant, antibacterial, and antidiabetic proper of S. elaeagnifolium have pest repellent and insecticidal prop
ties (Mueed et al., 2023). Therefore, herbal therapies are used erties against plant pests, they are used as alternatives to
worldwide to cure a variety of diseases and disorders synthetic pesticides to safeguard agricultural crops (Balah &
(Rondilla et al., 2021). AbdelRazek, 2020). The aerial parts of this plant, especially
Diabetes mellitus (DM) is a diverse and complicated public the leaves and seeds, harbor a variety of polyphenolic mole
health concern with significant socioeconomic implications. It cules, including kaempferol, kaempferol 8-C-b-galactoside,
has reached a health burden commensurate with the epi b-sitosterol, and stigmasterol (Balah & AbdelRazek, 2020).
demic diseases on a global scale (El Ghouizi et al., 2023). Although this plant is considered a weed, it contains various
Enzymatic digestion and absorption of carbohydrates by the compounds with remarkable medicinal properties. This deep-
intestinal mucosa play a role in postprandial glycemic regula rooted perennial plant has significant negative effects on
tion. This role has been considered in the diabetes treatment agricultural crops, causing yield declines of up to 75% in eco
approach, both in the development of nutrients and in the nomically important crops (Balah & AbdelRazek, 2020).
mechanism of action of oral antidiabetic drugs, which con Additionally, it competes intensely with other plants in geo
centrates on the action of the enzymes a-amylase and a-glu graphical regions (arid and irrigated areas) for water and vital
cosidase, as well as intestinal glucose transport (Sun & Miao, nutrients. Its invasive nature allows it to overtake natural
2020). As drugs for hyperglycemia already in the market habitats, often resulting in the dominance of native species
have adverse effects on humans, scientists and researchers by forming dense populations (Krigas et al., 2021).
are looking for new naturally sourced glucose-minimizing Although the crude extract of the plant has significant
compounds to block pancreatic a-amylase and gut a-glucosi therapeutic potential, it remains difficult to identify the spe
dase in hyperglycemic patients (Dwivedi et al., 2021). cific therapeutic phytochemicals that act as remedies for dis
Diabetics around the world are now using medicinal plant eases. Therefore, the pharmaceutical industry and scientists
extracts, which act as enzyme inhibitors in diabetes, to allevi rely solely on computer-aided drug design (CADD) to isolate
ate the complications caused by the severity of their dia molecules from therapeutically active extracts. Based on
betes (Benayad et al., 2021; Bouslamti et al., 2022; 2023; these facts, the present study aimed to explore the antidia
Hbika et al., 2022; Laaraj et al., 2022; Loukili et al., 2022; Sun betic potential of compounds identified from the leaf extract
& Miao, 2020). of Solanum elaeagnifolium after examining their inhibitory
On the other hand, free radicals are responsible for the potential against bacteria and diabetic enzymes such as
onset of arthritis, asthma, cancer, and diabetes (Bouslamti a-amylase and a-glucosidase.
et al., 2023). Components of the body, such as proteins, lip
ids, carbohydrates, DNA, and cell membranes, are denatured
by free radical oxidation. This is one of the main causes of 2. Materials and methods
aging by attacking the cells. Furthermore, the pancreatic cells
2.1. Sample collection and authentication
responsible for insulin are the first to be affected by the det
rimental effects of oxidative stress. However, the occurrence Plant samples were collected from Pithalaipatty village in the
of numerous diseases can be avoided by consuming natural Dindigul district of Tamil Nadu, India in June 2018. After prepar
by-products, such as leaves, fruits, and vegetables (Bouslamti ing the herbarium specimen, it was submitted to a taxonomist
et al., 2023). Therefore, the main aim of the current study at the Herbarium Center for Molecular Systematics, St. Josephs
was to investigate the pharmacological potential of Solanum College, Tiruchirappalli for authentication. Subsequently, a vou
elaeagnifoliu Cav., a plant whose therapeutic properties are cher specimen with herbarium number SB001 was preserved for
still relatively unexplored, as it is considered a weed. Because future reference (Supplementary Figure 1).
the plants grow unnecessarily along with the cultivated
crops, they are called weed plants. Aside from food crops,
2.2. Extract preparation
most plants used to treat diseases are collected from fallow
lands, forests, agricultural lands, and roadsides (Parthiban Fresh and mature leaves free of pathogens were selected
et al., 2016). To date, many plants have been effectively used and rinsed under running water to eliminate harmful sub
in traditional medicinal treatments, particularly weeds, as stances and debris. To transform the leaves into a finely
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS 3
ground powder for subsequent analysis, they were subjected was mixed with 0.5 mL of 1 N Folin-Ciocalteu reagent. After
to a 20-day drying period in a shaded room at temperatures adding 2.5 ml of 5% sodium carbonate solution to the mix
between 36 and 40 � C. Subsequently, the powder was ture, it was stored at 25 � C for 40 min, and the absorption
packed into the column of the Soxhlet apparatus for extrac was measured at 725 nm. To measure the total phenolic con
tion with a series of solvents, namely, acetone, ethanol, and tent, gallic acid was used as a reference for constructing the
ethyl acetate. To measure the total yield of the extract, the standard curve, and the total phenolic content was
following formula was used: expressed in gallic acid equivalents (mg GAE/g). The total fla
Amount of dried sampleðgÞ vonoid content in the SE leaf extract was assessed using
Yield of extract ð%Þ ¼ � 100 AlCl3 colorimetry (Amalraj et al., 2021a). For TFC determin
Amount of extract ðgÞ
ation, different concentrations of quercetin standard solu
tions were prepared at 20, 40, 60, 80, and 100 mg/mL. The
2.3. Chemicals and reagents extract and standard (quercetin) were combined with 2 mL
The reagents and chemicals, including Folin reagent, AlCl3 and 2 mL sodium acetate to yield a mixture of 1 mL
Ciocleteau’s Griess reagent, phosphate buffer, iron EDTA solu each. The absorption of the mixture was then measured at
tion, Nash reagent, sodium phosphate buffer, acetate buffer, 430 nm after storage at 25 � C for 30 min (Amalraj et al.,
p-nitrophenyl-a-D-glucopyranoside solution, dimethyl sulfoxide 2021a).
(DMSO), and NA medium were freshly prepared during the
experiment to evaluate the antibacterial and antidiabetic
2.5. Antioxidant activity
enzymatic properties of S. elaeagnifolium. For antioxidant ana
lysis, ascorbic acid served as a positive control, whereas acar The formation of reactive oxygen species (ROS) in the body
bose was used as a positive control to assess the antidiabetic leads to an oxidative stress response, which, under certain
enzyme activities of a-amylase and a-glucosidase. pathophysiological circumstances, could impair the function
of cells or organs (Figure 1). In the present study, the antioxi
dant potential of S. elaeagnifolium leaves extract was esti
2.4. Determination of total phenolics (TPC) and
mated by DPPH, FRAP, super oxide, phosphomolybdenum,
flavonoids content (TFC)
and metal chelating assays, as described by Amalraj et al.
To assess TPC, 1.0 mL of the extract or gallic acid standard (2021b). A brief description of the methodology of the
solutions at concentrations of 20, 40, 60, 80, and 100 mg/mL in vitro antioxidant assays is given below.
Figure 1. Sources of reactive oxidative stress that cause cell lysis.

4 F. X. T. ET AL.
2.5.1. Radical scavenging activity using the DPPH assay followed by the addition of 200 mL of 5 mM ferrozine; the
The evaluation of the DPPH scavenging properties of the total volume was adjusted to 3 mL. Subsequently, the reac
methanol formulation of S. elaeagnifolium leaves was carried tion mixture was blended completely and allowed to settle
out following a standardized procedure described by at room temperature for 10 min. The absorbance of the mix
Thangaraj (2016). Leaf extracts were prepared at different ture was measured at 562 nm after incubation. Ascorbic acid
concentrations with methanol, as follows: 50, 100, 150, 200, was used as the reference element for this assay. The evalu
and 250 mg/mL. The extract (100 mL) was combined with ation of the capacity to chelate metals was represented in
100 mL of a 0.1 mM DPPH solution and then stored in a dark EDTA equivalents (mg EDTA/g extract) and the results were
(36 � C) environment for 30 min. The absorbance of the mix compared to a reference graph.
ture was measured at a wavelength of 517 nm. The amount
of DPPH in the reaction solution was assessed using a cali
bration curve, with ascorbic acid as the reference compo 2.5.5. Total antioxidant activity by phosphomolybdenum
nent. The scavenging activity of S. elaeagnifolium was assay
measured and expressed as the IC50 value at the concentra The antioxidant properties of S. elaeagnifolium leaves were
tions used in this study. The percentage of inhibition of the examined using a phosphomolybdenum assay. 100 mL of
extract was determined using the following formula: extracts were combined with 1 mL of a reagent solution con
sisting of 28 mM sodium phosphate, 0.6 M sulfuric acid, 4 mM
Control OD − Sample OD
% Inhibition ¼ � 100 ammonium molybdate and a sufficient amount of 0.6 M
Control OD
H2SO4. Subsequently, the mixture was placed in a water
bath at 95 � C for 90 min and left to cool to room tempera
2.5.2. Superoxide radical scavenging activity ture. The absorption of the mixture was determined at a
Superoxide scavenging activity of the prepared plant extracts wavelength of 765 nm. As in the previous tests, ascorbic acid
was evaluated using the blue tetrazolium reduction tech was used as a standard reference. The results were reported
nique (Thangaraj, 2016). In this assay, 1 mL of leaf extract as equivalents of ascorbic acid per gram of extract (AAE/g),
was combined with 3 mL of a freshly prepared reaction mix with higher absorbance values indicating greater antioxidant
ture comprising 20 g riboflavin, 12 mM EDTA, and 0.1 mg) in capacity.
50 mM sodium phosphate buffer at pH 7.6. The samples
were then stored at 25 � C for 5 min. The absorbance of the
2.6. Anti-bacterial activity
mixture was measured at 590 nm. Ascorbic acid (AA) was
used as a reference component. The antibacterial potential of S. elaeagnifolium leaf extract
Control OD − Sample OD was determined using ethyl acetate, ethanol, and acetone.
Scavenging activity ð%Þ ¼ � 100 The prepared extracts were tested against three gram-
Control OD
positive bacteria, Bacillus subtilis (MTCC441), Rhodococcus
equi (MTTC2558), and Staphylococcus epidermis (MTCC435),
and seven gram-negative bacteria, Enterobacter aerogenes
2.5.3. Ferric reducing antioxidant power (FRAP) assay
(MTCC8559), Escherichia coli (MTCC40), Pseudomonas aerugi
TPTZ was used in this assay to evaluate the potential of the
nosa (MTCC1748), Proteus vulgaris (MTCC426), Salmonella
extracts to reduce Fe3þ to Fe2þ at pH values below 3.6. The
typhi (MTCC3224), Shigella flexneri (MTCC1457), and Vibrio
freshly prepared FRAP solution was formulated by mixing
cholerae (MTTC3904).
20 mM FeCl3, 10 mM TPTZ in 40 mM HCl, and 25 ml of 0.3 M
acetate buffer (adjusted to pH 3.6 using 0.3 M acetic acid
and 0.3 M sodium acetate) in a ratio of 1:1:10 v/v. 2.6.1. Minimum inhibitory concentrations (MICs)
Subsequently, the blend was left at 37 � C until it completely The inhibitory effect of S. elaeagnifolium leaf extract on bac
dissolved. First, 300 mL of the plant extract was combined teria was investigated using a 96-well microdilution method,
with the FRAP solution at concentrations of10, 20, 30, 40, as described by Amalraj et al. (2021b). To determine the con
and 50 mg/mL. The resulting reaction mixture was then left in centration required to suppress bacterial growth, 50 ml of
the dark at 37 � C for 30 min with the exclusion of light. The the extract was serially diluted twice at different concentra
absorbance of the mixture was measured at 593 nm wave tions. Subsequently, 50 mL of Mueller-Hinton broth was
length. FeSO7HO and ascorbic acid were used as reference added to each well containing the diluted extracts. The mix
elements in this assay. The results of this assay are expressed
tures were incubated for 24 h at 37 � C. Then, 20 mL of a
as moles of Fe (II) equivalents per milligram of extract.
0.5 mg/mL INT solution (p-iodonitrotetrazolium or 2-[4-iodo
phenyl]-3-[4-nitrophenyl]-5-phenyltetrazolium chloride) was
2.4.4. Metal chelating activity poured into all wells, slowly suspended, and allowed to
The ferrous ion-chelating capacity of S. elaeagnifolium was stand for 30 min. The mixtures were incubated again at
investigated following the method described by Amalraj 37 � C. After incubation, the wells treated with the plant
et al. (2021a). The extracts were initially prepared at concen extracts were compared with those treated with ampicillin
trations of50, 100, 150, 200, and 250 mg/mL. One milliliter of and examined for any color changes after the application of
the extract was combined with 50 mL of 2 mM FeCl2, the INT dye.
2.7. In vitro antidiabetic assays 1.2 mL/min as a carrier gas and functioned under a linear vel
ocity of 39.7 cm/s and pressure of 68.1 kPa (Adams, 2017). A
To measure the antidiabetic potential of S. elaeagnifolium
split ratio in the range of 1:10 was used, with one milliliter
leaf extracts, a-amylase and a-glucosidase enzyme inhibition
(1 mL) of leaf extract suspended in hexane injected into the
assays were performed according to the method described
gas chromatograph (GC) (Adams, 2017). The mass spectrum
by Krupa et al. (2022). In this in vitro antidiabetic assay,
was developed in electron ionization (EI) mode at 70 electron
starch and p-nitrophenyl-a-d-glucopyranoside (PNPG) were
volts (eV) and acquired over a mass range of 50–500 (amu).
used as substrates, and acarbose was used as a reference
drug. The temperature of the ion source was maintained at 200 � C.
Interpretation of the compounds was performed by compar
ing the compounds identified in the leaf extracts of SE with
2.7.1. Inhibitory assay of a-amylase the reference spectra available in the NIST 2005 Mass
In this assay, 100 mL of S. elaeagnifolium leaf extract was incu Spectral Library and relevant literature. The relative propor
bated at 25 � C for 10 min at various concentrations with a tions of compounds were determined by averaging the peak
1% starch solution in a 20 mM phosphate buffer (pH 6.9 areas and expressing the proportion of each compound as a
containing 6 mM NaCl). Subsequently, 100 mL of amylase percentage of the total chromatogram area.
(0.5 mg/mL) was introduced, and the mixture was further
incubated at 25 � C for 10 min. Next, 200 mL of dinitrosalicylic
acid reagent was blended to arrest the hydrolytic reaction,
and the resulting mixture was incubated at 100 � C for 5 min. 2.9. In silico antidiabetic validation
Subsequently, the samples were allowed to cool to room 2.9.1. Biological data
temperature. Subsequently, a 50 mL aliquot of the reaction The chemical components of S. elaeagnifolium leaves
mixture was transferred to a microplate with 96 wells. This detected by GC-MS and diabetic drugs were collected from
was followed by dilution with 200 mL distilled water. The the Chemspider database in the mole format (http://www.
absorbance was measured at 540 nm. The following formula chemspider.com). Similarly, diabetic proteins, namely pancre
was used to determine the degree of a-amylase inhibition
atic alpha-amylase, glycogen phosphorylase B, and phos
caused by S. elaeagnifolium leaves.
phorylase kinase, were extracted from the protein repository
Absorbance of extract database. The alphanumeric codes of the diabetic proteins
% Activity ¼ � 100
Absorbance of control are 1B2Y (Figure 2), 1H5U (Figure 3), and 1QL6 (https://www.
rcsb.org).
2.7.2. Inhibitory assay of a-glucosidase

In this assay, various concentrations of S. elaeagnifolium
leaves extracts were combined with 100 mM sodium phos 2.9.2. Docking and modeling platform
phate buffer (pH 6.9) in the reaction mixture. To initiate the This study was performed using Maestro V.13.2 modules
hydrolytic reaction, 50 mL of 5 mM PNPG solution (dissolved entailing LigPrep, Grid Generation, SiteMap, and Glide XP.
in phosphate buffer) was added. The resulting mixture was After installing this software in the highly configured Linux
incubated at 37 � C for 5 min. Subsequently, 100 mL of phos operating system, we investigated the antidiabetic potential
phate buffer containing 0.1 U/mL a-glucosidase was added of phytochemicals in S. elaeagnifolium leaves. Each module
to each well. After a further 30-minute incubation period, the of this software was employed to prepare ligands and pro
absorbance at 405 nm was measured. The percentage of tein molecules in specific operations, such as ligand prepar
a-glucosidase inhibition by the extracts was calculated using ation, protein preparation, site map analysis, and gride
the following formula: generation process (Kalaimathi et al., 2021; 2022a).
Absorbance of extract
% Activity ¼ � 100
Absorbance of control
2.9.3. Target preparation
Water molecules were removed from diabetic proteins using
2.8. Gas chromatography–mass spectrometry (GC–MS) the Protein Preparation Wizard module. Proteins that tangled
Shimadzu (QP2020) was used to carry out the GC-MS analysis water molecules were unsuitable for the transition to the
of the S. elaeagnifolium leaf extract interfaced with a mass docking process. These were then removed from the super
spectrometer. SH-Rxi-5Sil-MS was used as a non-polar capil natant. In this step, two phases were implemented, prepar
lary column with a length of 30 m and an inner diameter of ation and refinement. These were used to find missing
0.25 mm. The column has a film thickness of 0.25 micro residues, build the amino acid sequences, and update the
meters (m) and is completely layered with polydimethylsilox missing residues in the proteins currently being studied.
ane (100%). The initial oven temperature was maintained at Additional steps, including optimization and minimization
50 � C and then increased to 280 � C at a rate of 6 � C/min, phases, were also performed to capture the structured pro
with a final hold time of 2 min. The injector temperature was tein for further evaluation (Christy Rani et al., 2022;
set at 250 � C. Helium was sustained at a stream rate of Kalaimathi et al., 2022a).
6 F. X. T. ET AL.
Figure 2. Residues of human pancreatic alpha-amylase (PDB ID: 1B2Y).
Figure 3. Residues of glycogen phosphorylase B (PDB ID: 1B2Y).
2.9.4. Active site prediction the appropriate binding site for grid generation from the
This is essential for the grid generation. Therefore, the cata binding sites, all sites were evaluated considering their site
lytic ligand sites on diabetic proteins were examined using volumes and scores (Kalaimathi et al., 2022a). The grid site
the Sitemap tool. The final product of the protein prepar residues of human pancreatic alpha-amylase are ARG195,
ation was evaluated. Although the protein has a significant ASP197, ALA198, GLU233, ILE235, GLY306, HIE305, TRP357,
number of ligand-binding cavities, not all of them could be ASP356, GLN63, TYR62, TRP59, and TRP58; whereas the grid
recognized as ligand-binding cavities in this study. To select site residues of glycogen phosphorylase B are HIP34, LYS574,
GLY675, THR676, GLY677, LYS680, LEU136, GLY135, LYS568, extra Naþ/Cl- ions, to neutralize the systems. The particle
ARG138, ALA653, VAL650, ARG649, TYR648 and THR378. network Ewald method was used to calculate long-range
electrostatic interactions, while a cutoff radius of 9.0 was
used for short-range van der Waals and Coulomb interac
2.9.5. Grid generation tions. Each solvated system underwent a minimization and
The lattice boxes were designed through the lattice module
equilibrium process following Desmond’s standard protocol
to stabilize the binding sites in the diabetic proteins with in Maestro V13.7, which consisted of two NVT-and two NPT-
focal points of X:19.26, Y:7.59, and Z:48.56 for 1B2Y and constrained short simulations. Subsequently, all equilibrated
X:11.49, Y:18.05, Z:16.02 for 1QL6. It was built to dock the systems in the NPT ensemble were subjected to molecular
ligands to the catalytic site of diabetic proteins. This process dynamics (MD) simulations under periodic ensemble bound
has been successfully implemented based on the knowledge ary conditions using the OPLS4 force field for a duration of
gained to date (Sangeetha et al., 2018). 100 nanoseconds (ns). The simulations were carefully con
trolled to maintain a temperature of 300 K and a pressure of
2.9.6. Ligand preparation 1 atm. This was achieved using the Nos-Hoover chain
This task was executed using the LigPrep (2.4) module. After thermostat to control the temperature and Martyna-Tobias-
the ligand was obtained in the molar format, it was sub Klein’s barostat techniques to control the pressure. The bind
jected to alignment before being docked. The OPLS2005 ing energy between diabetes-related proteins and phyto
force field was applied to refine the structure of the acquired chemicals was measured over a 100-ns simulation time
ligand. In this module, the 3D structures of ligand molecules frame (Pirolli et al., 2023).
were generated from their 1D (Smiles) and 2D (SDF) repre
sentations. Two key mechanisms, tautomers and stereoisom 3. Results and discussion
ers, have been used to reduce the structural complexity of
ligands, thereby optimizing their physical density. After each 3.1. Yield of crude extracts
input molecule was thoroughly analyzed, a ligand molecule The yield of the crude extract obtained from the leaves of S.
with a specific molecular mass or precise number and elaeagnifolium was 6.80% for ethanol, 4.97% for acetone, and
arrangement of functional groups, as well as the required 4.77% for ethyl acetate extracts (Table 1). This corroborates a
stereochemical composition, was collected for further study similar report by Bouslamti et al. (2022), who obtained a
(Kalaimathi et al., 2022b). yield of 10.2% for hydroethanolic and 9.36% for hydroace
tonic leaf extracts od the leaves. They also reported that the
2.9.7. Molecular docking extraction yield varied depending on the solvent and plant
Molecular docking was performed using the Maestro V.13.7 part. In accordance with this statement, the present study
Grid Glide docking unit. In this study, the Xtra precision shows that yields vary depending on the polarity of the sol
vents used.
mode (XP) was used to determine the drug affinities
between the phytochemicals and diabetic proteins. As
reported in previous studies, drug-grade molecules were fil 3.2. Total phenolics and flavonoids contents
tered based on their drug metrics, including docking scores,
sliding energy, and hydrogen bonds (Kalaimathi et al., TPC was calculated using the standard curve of the linear
2022b). regression equation (y ¼ 0.0222 � −0.0414, R2 ¼ 0.9646) and
expressed as milligrams per gram equivalent of gallic acid
(Table 1). The ethanolic extract yielded the highest TPC
2.9.8. MD simulations (158.77 ± 1.46 mg/g GAE), followed by ethyl acetate
Molecular dynamics (MD) simulations for the top-rank ligand- (79.04 ± 0.98 mg/g GAE) and acetone extracts
protein complexes were performed using Desmond 6.8 (41.78 ± 0.14 mg/g GAE). Similar to TPC, TFC was calculated
module implemented in Maestro V13.7. The ligand-protein using the standard curve of the linear regression equation
complexes were placed in a cubic water enclosure with a 10- (y ¼ 0.0319 � −0.05254, R2 ¼ 0.9792) and determined as
unit buffer gap to enable simulations, and then SPC water milligrams per gram equivalent of quercetin (Table 1). The
models were used to solvate the complexes. Additionally, a ethyl acetate extract had the highest TFC (134.31 ± 0.04 mg/g
salt concentration of 0.15 M NaCl was supplied, as well as QE), followed by the ethanol (120.03 ± 0.73 mg/g QE) and
Table 1. Yield, total phenolic and flavonoid content, a-amylase and a-glucosidase activities of S. elaeagnifolium leaf extracts.
Solvents Yield of extract % TPC mg/g GAE$ TFC mg/g QE# a-amylase IC50 (mg/ml)� a-glucosidase IC50 (mg/ml)�
Ethyl acetate 4.77 79.04 ± 0.98 134..31 ± 0.04 41.56 ± 1.63ab 59.76 ± 13.66ab
Ethanol 6.80 158.77 ± 1.46 120.03 ± 0.73 17.78 ± 2.38a 27.90 ± 5.02a
Acetone 4.94 41.78 ± 0.14 116.39 ± 0.48 17.96 ± 6.05a 36.44 ± 3.30b
Acarbose NA NA NA 15.28 ± 0.43 14.51 ± 0.23
$
milligram per gram equivalent of gallic acid.
#
�
milligram per gram equivalent of quercetin.
The Inhibitory concentration of the sample required to inhibit the enzymes activity by 50%. The values of result mentioned as means (n ¼ 3) ± standard deviation.
Same letters as superscript in same column (for different extracts/samples); NA: Not Applicable.
8 F. X. T. ET AL.
acetone extracts (116.39 ± 0.48 mg/g QE). The total polyphe 0.122 ± 0.021 mg/mL. In another study by Bouslamti et al.
nols and flavonoids in S. elaeagnifolium leaves were exam (2022), hydroethanolic extracts of leaves and fruits were used
ined using different solvents, such as hydroethanol and to evaluate the antioxidant activity. It was found that the
hydroacetone (Bouslamti et al., 2022). It was previously free radical scavenging activity was significantly reduced by
reported that the total polyphenols in the hydroethanolic both extracts (leaves and fruit hydroethanolic extracts) with
formulation was found to be 2.54 ± 0.4 mg (EAG/g extract), IC50 values of 35.15 ± 60.9 mg/mL and 132.46 ± 11.73 mg/mL
whereas the amount of total polyphenols in the hydroace respectively. However, in the present study, ethyl acetate
tonic formulation was found to be 1.58 ± 0.03 mg (EAG/g extract of S. elaeagnifolium leaves showed significant antioxi
extract). The TFC was also determined with these two formu dant potential with an IC50 value of 16.62 ± 0.25 mg/mL,
lations and the results revealed that the TFC in the hydroe which is better than the previously and currently used stand
thanolic formulation was 0.012 ± 0.001 mg (EAG/g extract), ards, namely, butylated hydroxytoluene (BHT) and ascorbic
whereas the total polyphenols in the hydroacetonic formula acid.
tion was 0.067 ± 0.01 mg (EAG/g extract). Similar to Bouslamti
et al. (2022), differences in the TPC and TFC of two different
extracts, ethanol and ethyl acetate, were also observed in 3.3.2. Superoxide radical scavenging assay
the present study. In particular, the ethyl acetate formulation The ethanolic formulation achieved the notable antioxidant
yielded the highest total flavonoid (TFC) content. Conversely, effects with IC50 values of 33.96 ± 4.5 mg/mL followed by
the highest phenol yield was observed for the ethanol for ethyl acetate (19.61 ± 1.61 mg/mL) and acetone
mulation. Based on these reports, we found that the yield of (16.13 ± 11.05 mg/mL) (Table 2). In general, superoxide anions
phytochemicals varied depending on the polarity of the solv are detrimental to cellular components. According to Robak
ent (Sultana et al., 2009). and Gryglewski (1988), flavonoids are considered effective
antioxidants because they actively neutralize superoxide
anions. The results of this study confirm the previous claim
3.3. Antioxidant effects of Solanum eleagnifolium by showing that the plant extract prepared with ethanol is a
3.3.1. DPPH radical scavenging assay more effective scavenger of superoxide radicals than the
The hydrogen donation or radical scavenging effect of S. ele standard, mainly because of the presence of flavonoids. In
agnifolium leaves was determined using the DPPH approach. contrast to the present research, Houda et al. (2014) explored
The DPPH scavenging effect was quantified and expressed as the antioxidant activity of S. elaeagnifolium seeds. They used
an IC50 value, which represents the concentration of the almost six solvent extracts, including hexane, dichlorome
sample required to achieve 50% inhibition, and was deter thane, ethyl acetate, acetone, and aqueous solutions. End of
mined through interpolation from a linear regression ana the assays, the acetone extracts shows notable antioxidant
lysis. A lower IC50 value indicates a higher radical scavenger effects with an IC50 values of 0.025 mg/mL. The total antioxi
activity. According to this finding regarding the antioxidant dant capacity of each solvent was analyzed at doses of
activity of SE leaf extract, the leaf extract formulation with 0.0125, 0.025, 0.05 mg/mL and 0.1 mg/mL. Alpha-tocopherol,
ethyl acetate achieved the notable antioxidant effects, with an important phytochemical of S. elaegnifolium, was treated
an IC50 value of 16.62 ± 0.25 mg/mL, followed by ethanol with plant extracts at the same dosage in this study to inves
(40.32 ± 0.12 mg/mL) and acetone (103.81 ± 0.47 mg/mL) tigate the antioxidant capacity of the extracts. Finally, the
(Table 2). Similarly, antioxidant effects of S. elaeagnifolium acetone extracts showed remarkable antioxidant capacity
leaves were reported by Bouslamti et al. (2022). For this with values of 107.93 ± 0.65 mg/mL (Houda et al., 2014).
assay, they used two solvent extracts: hydroethanolic and Based on their findings, they reported that the acetone
hydroacetonic. In their research, it was found that the hydro extract of the seeds contained high levels of phenolic and
ethanolic extract had a remarkable antioxidant potential with flavonoid compounds, which also played an important role
an IC50 value of 0.0807 ± 0.0039 mg/mL, which is better than in scavenging free radicals. On the other hand, previous
that of the hydroacetonic extracts. However, the hydroetha studies have demonstrated significant hydrogen peroxide
nolic and hydroacetonic formulations showed minimal anti scavenging activity and strong antioxidant potential in vari
oxidant potential compared to the corresponding ous species of the genus Solanum, including Solanum
antioxidant, butylated hydroxytoluene (BHT), in which BHT aethiopicum, Solanum macrocarpon and Solanum torvum,
showed antioxidant potential with an IC50 value of with recorded percentages of 61.5%, 45.8%, and 35.2%,
Table 2. Total antioxidant activity of S. elaeagnifolium leaf extracts.

Solvents DPPH SO FRAP PHM MC
Ethyl acetate 16.62 ± 0.25a 19.61 ± 1.61b 995.67 ± 50.82c 100.70 ± 9.97a 539.33 ± 6..67e
Ethanol 40.32 ± 0.12ab 33.96 ± 4.5a 278.52 ± 42.87c 109.78 ± 10.60a 445.44 ± 3.47c
Acetone 103.81 ± 0.47ab 16.13 ± 11.05b 847.10 ± 28.58c 168.67 ± 1.92a 663.50 ± 10.93e
Ascorbic acid 13.23 ± 0.35 11.34 ± 0.75 1127.10 ± 11.64 147.56 ± 0.0 357.39 ± 2.10
Values in IC50 (mg/mL); DPPH - Radical scavenging activity using 2,2-diphenyl-1-picrylhydrazylmethod; SO - Superoxide radical scavenging
activity (mg/ml); PHM - Phosphomolybdenum assay (mg/g); FRAP - Ferric reducing-antioxidant power assay (mM Fe (II) E/mg); MC - Metal
chelating activity (EDTA E mg/g). Values are expressed as mean (n ¼ 3) ± standard deviation; same letters as superscript in same column
(for different extracts/samples) are not significantly different according to Tukey’s test (p < 0.0001).
respectively (Khatoon et al. 2018; Mandal et al., 2008; with values of 168.67 ± 1.92 mg/g, followed by ethanol
Muruhan et al., 2013). (109.78 ± 10 mg/g) and ethyl acetate (100.70 ± 9.97 E/g)
extracts. In recent antioxidant-based research on night
shades, an ethanol extract of the fruit Solanum nigrum was
3.3.3. Ferric reducing antioxidant power assay (FRAP) used at doses of 20, 40, 60, 80, 100, and 120 mg/mL to
Further evaluation of the reducing power of S. elaeagnifolium
reduce the effect of phosphomoldenum (Sivaraj et al., 2020).
leaf extracts was performed using the FRAP assay. The max
At the end of the assay, the phosphomoldenum was signifi
imum FRAP value in the leaves of S. elaeagnifolium formu
cantly reduced by 96.77 ± 6.77% at a dose of 120 mg/mL;
lated with ethyl acetate was found to be 995.67 ± 05.82,
whereas, the RC50 value of the extract was found to be
followed by acetone extract (847.10 ± 28.58) (Table 2). The
21.25 mg/mL (Sivaraj et al., 2020).
FRAP values were higher than those of the other extracts
Moreover, the ability to chelate or deactivate transition
examined. The standard ascorbic acid was also found to
metals, particularly Fe (II), which can accelerate the decom
have a significant FRAP effect (1127.10 ± 11.64 mg/mL).
position of hydrogen peroxide, is the key mechanism for the
Bouslamti et al. (2022) reported that hydroacetone extracts
antioxidant effect. Therefore, this assay plays a crucial role in
showed remarkable antioxidant activity in the FRAP assay
assessing the Fe (II)-chelating properties of extracts.
with an EC50 value of 0.08256 ± 0.005105 mg/mL, whereas
Endogenous chelating compounds, particularly phenols, are
hydroethanol extract had a lower reducing effect than hydro
responsible for the Fe (II)-chelating properties of the extract.
acetone extract (EC50 value of 0.1157 ± 0.0400 mg/mL).
In this assay, the reduced absorption of the ferrozine com
However, these two extracts had a lower reducing effect,
plex, which occurs when antioxidants compete with ferrozine
comparable to that of butylated hydroxytoluene
to chelate iron ions, was used to quantify the Fe2þ-chelating
(EC50 ¼ 0.362 ± 0.010 mg/mL). Based on their observations,
activity of the extracts (Khatoon et al., 2018; Mohyuddin
they documented that these two extracts contained moder
et al., 2022). In the metal chelation assay of the present
ate levels of polyphenols and flavonoids. In another study by
research, a significant activity was found in the acetone
Bouslamti et al. (2022), the leaves and fruits of S. elaeagnifo
extract (663.50 ± 2.1 mg/mL), followed by ethyl acetate
lium were used to assess the antioxidant activity. These two
(539.33 ± 6.67 E/g) and ethanolic extracts (445.44 ±
components were extracted using a maceration process with
3.47 mg/mL) (Table 2). Finally, the present study showed that
70% methanol. It was then prepared as a hydroethanol
all the studied extracts had a stronger metal-chelating poten
extract. In the antioxidant FRAP assay, these two extracts
tial than the standard ascorbic acid. Previously, the metal-
showed notable reducing effects with EC50 values of
chelating activity of the fruits of three Solanum species
83.46 ± 7.69 mg/mL and 462.36 mg/mL respectively. In add
namely S. torvum, S. aethiopicum and S. macrocarpon was
ition, the FRAP assay was performed at different stages of
investigated by Khatoon et al. (2018). Among the extracts
the fruit (unripe, ripe, and overripe) of S. elaeagnifolium (Feki
examined, S. athiopicum was found to have the highest
et al., 2014). Different seed extracts, such as cyclohexane,
metal-chelating activity (39.4%), followed by S. torvum
dichloromethane, ethyl acetate, methanol, and aqueous,
(24.5%) and S. macrocarpon (12.3%). Sowndhararajan and
were employed in this assay; however, they also used ascor
Kang (2013) reported that the antioxidant effects of plant
bic acid as a standard, similar to the present study. At the
extracts especially the radical scavenging and metal chelat
end of the assay, it was found that the methanol extracts of
ing effects, may vary due to the presence of a unique phen
all fruit stages had significant effects on the reduction of
olic structure and the quantity of hydroxyl groups in the
Fe3þ/ferricyanide complexes, with EC50 values ranging from
phytocomponents of the respective extracts.
0.39-0.53 mg/mL. However, it was found that the reducing
effect of the methanol extract was two to three times better
than that of ascorbic acid at all stages. The half-maximal 3.4. Minimum inhibitory concentration of
effective concentration (EC50) of ascorbic acid was S. elaeagnifolium
1.56 mg/mL. This finding shows that the remaining extracts
The minimum inhibitory dose of S. elaeagnifolium leaves
significantly reduced the antioxidant effect. They also
against the bacterial strains employed in this study was
reported that solvent polarity and fruit ripening had a signifi
determined after formulation with different solvents, such as
cant influence on phenolic content and antioxidant activity.
acetone, ethanol, and ethyl acetate. Table 3 shows the inhibi
tory doses of the plant extracts against the growth of the
3.3.4. Phosphomolybdenum assay and metal-chelating selected bacterial strains. At the end of the MIC evaluation,
activity the ethanol formulation, at a dose of 29.687 mg/mL, showed
Phosphomolybdenum is known to be a complex assay that a noticeable inhibitory effect against Pseudomonas aerugi
generally helps in the detection of ascorbic acid, tocopherol, nosa. Conversely, the ethanol formulation at a concentration
phenols, and carotenoids and is used to identify the total of 59.375 mg/mL significantly suppressed V. cholera growth.
antioxidant activity of the extracts (Khatoon et al., 2018). The The inhibitory effect of the extract can be recognized by the
total antioxidant effects of S. elaeagnifolium leaves were color changes in the well after treatment with the extracts in
examined after extraction using different solvents, and the bacterial strain-growing wells. If the wells turned red-pink, it
results are shown in Table 2. In which, a notable phospho indicated bacterial growth, whereas the absence of color in
molybdenum effects were observed in acetone formulation the well indicated no bacterial growth. Consistent with this
10 F. X. T. ET AL.
Table 3. Antibacterial activity of S. elaeagnifolium leaf extracts by minimum inhibitory concentration.

Minimum inhibitory concentration (mg/ml)
Formulated Extracts EC PV SE BS RE VE ST SF PA EA
Ethyl acetate 237.5 118.75 475 237.5 >950 475 950 475 >950 >950
Ethanol 118.75 118.75 118.75 118.75 118.75 59.375 950 118.75 29.6875 59.375
Acetone 237.5 118.75 475 237.5 >950 475 475 237.5 >950 >950
Ampicillin 7.5 7.5 7.5 7.5 7.5 7.5 1.875 3.75 3.75 7.5
EC - E.coli; PV - Proteus vulgaris; SE - Staphylococus epidermis; BS - Bacillus subtilis; RE - Rhodococcusequi; VC – Vibrio cholera; ST - Salmonella typhi; SF – Shigella
flexneri; PA - Pseudomonas aerogenes; EA –Enterobactera eroegenes.
Figure 4. The minimum inhibitory concentration range of S. elaeagnifolium extracts in different solvents.
statement, color changes in the MIC exploration are shown the phytoconstituents of the plant samples and their bac
in Figure 4. Previously, Alajmi et al. (2018) stated that the tericidal action. In addition, phytochemicals can manifest
color changes in the well might be due to the solubility of their bactericidal action either alone or in extracts
formulated synergistically with other phytochemicals (Alajmi 40.31 ± 2.04 mg/mL. Furthermore, a-amylase activity was
et al., 2018). inhibited by 63% in leaves and 84% in flowers, with IC50 val
According to Bouslamti et al. (2022), extract formulations, ues of 79.16 ± 40.31 and 99.16 ± 1.17 mg/mL. In contrast, acar
such as hydro-ethanol and hydro-acetone, showed remark bose reduced the enzymatic activity of a-amylase by 65%.
able antibacterial effects that were close to those of standard Although acarbose has a weaker amylase inhibitory effect
erythromycin. In particular, hydroacetonic acid showed a than plant extracts, it has a significant IC50 value of
maximal zone of inhibition against Bacillus subtilis, with a 44.65 ± 0.01 mg/mL than leaf and flower extracts (Bouslamti
diameter of 10.5 ± 0.50 mm. It inhibited the growth of et al., 2023). Selvi and Yogananth (2016) previously investi
Bacillus subtilis at a dose of 7.5 ± 0.00 mg/mL. Similarly, the gated the antidiabetic potential of the stems and leaves of
hydroethanolic extract demonstrated its inhibitory potential other species of this genus, namely S. nigrum. Their research
against Proteus mirabilis with an inhibition zone of showed that the percentage inhibition of a-amylase
8.25 ± 0.75 mm, whereas the MIC of this extract against increased as the concentration of the extract increased.
Proteus mirabilis was 15 ± 0.00 mg/mL. Bouslamti et al. (2022)
reported that a hydroacetonic extract had a stronger antibac
terial effect than a hydroethanolic extract of S. elaeagnifolium 3.5.2. a-Glucosidase inhibition effect
leaves. The S. elaeagnifolium leaf extract was used to study a-glyco
sidase enzyme inhibition after extraction with acetone, etha
nol, and ethyl acetate. In this assay, the extracts of the
3.5. In vitro antidiabetic activity of Solanum ethanolic formulation had a noteworthy inhibitory effect of
elaeagnifolium 66.87% at 50 mg/mL, and the result was expressed as the
IC50 value. As a glucosidase inhibitor, the ethanolic extract
To the best of our knowledge, no research on the antidia
exhibited a remarkable IC50 value at a dose of 27.90 mg/mL
betic activity of S. elaeagnifolium, particularly a-amylase and
(Table 1 and Figure 5). The results clarified that the leaves of
a-glucosidase assays, has been performed previously (ref.)
the plant could significantly reduce the risk of diabetes by
suppressing the enzyme a-glycosidase. The inhibitory effect
3.5.1. a-amylase inhibition activity of S. elaeagnifolium leaves, flowers, and fruits on intestinal
The leaf extract of S. elaeagnifolium was formulated with a-glucosidase was previously investigated at doses of 200,
acetone, ethanol, and ethyl acetate to study its antidiabetic 400, 600, and 800 mg/mL (Bouslamti et al., 2023). All the
effects in terms of suppressing the enzymes responsible for tested extracts were reported to have notable a-glucosidase
diabetes, a-amylase, and a-glucosidase. The inhibitory doses effects at all treatment doses. The extracts were found to
of each formulation are shown in Table 1. Table 1 shows have a consistent percentage of a-glucosidase inhibition of
that the formulations containing acetone and ethyl acetate 80% at doses of 200-400 mg/mL. Among the extracts, leaves
were identified as strong inhibitors of a-amylase activity. In and fruits exhibited notable IC50 doses of 20.05 ± 0.12 mg/mL
this assay, the ethyl acetate extract significantly inhibited and 20.53 ± 0.37 mg/mL. In contrast, acarbose reduced the
a-amylase activity by 42% with an IC50 value of enzymatic activity of a-amylase by 90%. However, it has
41.56 ± 1.63 mg/mL. In contrast, acarbose was found to have exhibited higher IC50 values (52.56 ± 2.67 mg/mL) than all the
the lowest percentage of a-amylase inhibitory effects (19%) three extracts, meaning it is no better than the extracts of S.
compared with other plant extracts, namely ethanol (20%) elaeagnifolium.
and acetone (20%) (Figure 5). The inhibitory concentration of Similar to the present study, several other species of the
extracts was defined as the sample concentration required to genus Solanum, including S. torvum (Satyanarayana et al.,
elicit 50% inhibition, at which point the highest inhibition 2022) and S. trilobatum (Rajasulochana et al., 2021), S. virgin
was recorded as the IC50 value (Table 1). The inhibitory ianum (Saraswathi et al., 2021), S. surratense (Sridevi et al.,
effect of S. elaeagnifolium leaves, flowers, and fruits on pan 2011), S. nigrum (Selvi & Yogananth, 2016), and S. xanthocar
creatic a-amylase was previously investigated at doses of pum (Selvi & Yogananth, 2016) have been used to evaluate
200, 400, 600, and 800 mg/mL (Bouslamti et al., 2023). Among their antidiabetic effects in in vivo and in vitro models.
them, the fruit extracts were reported to have a remarkable According to Satyanarayana et al. (2022), the ethanolic
a-amylase inhibitory effect (84%) with an IC50 value of extracts of S. torvum fruits were found to have a significant
antidiabetic effect by reducing blood sugar levels, total chol
esterol, and triglycerides; however, histopathological observa
tions showed that they also regenerated the b-cells of the
islets of Langerhans. Recently, the antidiabetic effect of the
aerial parts of S. trilobatum was studied after S. trilobatum
was cultured by micropropagation (Rajasulochana et al.,
2021). According to the results, the aerial parts of the micro-
propagated plant showed significant anti-diabetic effects by
reducing the activity of the enzymes a-amylase and a-gluco
Figure 5. a-amylase and a-glucosidase inhibitory activity of Solanum elaeagni
folium leaf extracts at different concentrations. Values are expressed as sidase, just as the antidiabetic effects of wild plant
means ± SD (n ¼ 3). (Rajasulochana et al., 2021).
12 F. X. T. ET AL.
3.6. GC–MS detected phytochemicals of Solanum kaempferol, rutin, quercetin-3-O-beta-glucoside, quercetin,

elaeagnifolium leaves and sinapic acid. In comparison with the report by Bouslamti
et al. (2023), the present study found that, with the excep
In this study, 23 phytochemicals were detected in the etha
tion of cinnamic acid, all the phytochemicals of leaves, such
nol extract by GC-MS (Figure 6). The detailed values of the as salicylic acid, ferulic acid, sinapinic acid, chlorogenic acid,
phytochemicals, including the peak areas and molecular for and rutin, exist alternately in flowers and fruits. On the other
mulas and the structures of the identified chemical constitu hand, sinapinic acid and chlorogenic acid are widely distrib
ents, are shown in Table 4 and Figure 7. Among the uted in aerial parts including leaves, flowers and fruits.
identified chemical constituents, solanesol, a unique chemical Numerous in silico, in vitro, and in vivo studies have shown
constituent of the Solanum genus, has been previously that sinapinic acid and chlorogenic acid have anti-oxidant,
shown to suppress the growth of Escherichia coli and anti-tumor, hepatoprotective, nephroprotective, anti-dengue,
Pseudomonas aeruginosa (Chen et al., 2017). Previous phyto anti-bacterial, anti-diabetic, anti-inflammatory, anti-breast
chemical profiling of Solanum elaeagnifolium was quite close cancer, cerebral protective, hypoglycemic, anti-cardiovascular,
to the phytochemicals reported in the present study, but anti-mutagenic, immunomodulatory, and anti-hyperlipidemic
they employed ethyl acetate and 25% methanol/ethyl acet effects (Chen, 2016; Miao & Xiang, 2020; Tajik et al., 2017).
ate fractions, which was in contrast to the present study The present study also contrasts with the phytochemical
(Badawy et al., 2013). A recent study by Bouslamti et al. investigation of Bouslamti et al. (2023), with dissimilar repres
(2023) found that the leaves of S. elaeagnifolium contain sion of phytoconstituents. However, some therapeutically
therapeutically important polyphenolic molecules, namely, important phytochemicals such as c-sitosterol, a-amyrin,
chlorogenic acid, cinnamic acid, ferulic acid, rutin, salicylic a-tocopherol, Betulin, stigmasta-5, 22-dien-3-ol (stigmasterol),
acid, and sinapic acid. In addition, they reported that the and campesterol were identified in the present research in
flowers were rich in ferulic acid, chlorogenic acid, GC-MS analysis.
Figure 6. GC-MS peak areas of the ethanol extracts of S. elaeagnifolium.
Table 4. GC-MS analysis of S. elaeagnifolium ethanol leaf extract.

Peak Retention time % Peak area Molecular Mass Name of the Compound
1 5.589 0.2 101 N,N-diethyl-Formamide,
2 6.942 1.14 115 N,N-diethylcetamide,
3 7.691 0.89 108 Benzenemethanol
4 17.522 0.16 518 Tetradecamethyl-Cycloheptasiloxane,
5 20.769 0.38 592 Hexadecamethyl-Cyclooctasiloxane,
6 23.574 1.54 666 Octadecamethyl-Cyclononasiloxane,
7 26.067 0.24 740 Icosamethylcyclodecasiloxane
8 26.517 0.24 278 1,2-benzenedicarboxylicacid,dibutylester
9 28.347 0.37 592 Tetracosamethyl-Cyclododecasiloxane,
10 28.928 18.09 414 Gamma-sitosterol
11 31.166 30.86 630 Solanesol
12 31.75 1.74 290 Geranyllinaloolisomerb
13 32.804 19.36 546 Lycopersene
14 34.641 0.96 330 Hexadecanoic acid, 2,3-dihydroxypropyl ester
15 34.877 0.48 390 1,2-Benzenedicarboxylicacid, diisooctylester
16 34.983 0.75 272 M-Camphene
17 35.634 1.13 368 1-Pentacosanol
18 36 0.84 430 Alpha-Tocopherol
19 36.13 2.04 426 Alpha-amyrin
20 36.228 2.19 442 Betulin
21 38.418 3.44 400 Campesterol
22 38.61 1.99 440 Cyclolaudenol
23 39.108 6.03 412 Stigmasta-5, 22-dien-3-ol
Figure 7. Structure of phytochemicals detected by GC-MS from the ethanol leaf extracts of S. elaeagnifolium.
3.7. In silico molecular docking studies instance, in the ligand-based drug discovery algorithm, quer
cetin was found to be an effective drug for the proteins
To predict which ligands are likely to bind to a target protein responsible for diabetes, such as glycogen phosphorylase
and either block or trigger specific enzymes or genes as part (1NOI) and PPARc (3G9E). Accordingly, it was administered in
of the ligand-based drug development process, researchers, a dose-dependent manner to rats with streptozotocin-
particularly in the field of drug development, often rely on induced diabetes after being isolated from the fruits of
molecular docking scores and binding energies (Devaraji Phyllanthus embilica L. Finally, administration of quercetin at
et al., 2023). To reduce the cost of money and time and a dose of 75 mg/g significantly reduced hyperglycemia in dia
avoid complicated wet lab experiments, researchers usually betic rats by increasing the rate of insulin secretion and the
use molecular docking algorithms to find small molecules function of b-cells in the pancreas (Prabhu et al., 2018). This
that are effective against diseases (Devaraji et al., 2023). preclinical investigation helped to identify a suitable drug
Specifically, this also minimizes the failure rate of drugs in candidate for administration to diabetic rats. Therefore, we
the final stages of clinical trials (Rifaioglu et al., 2019). For believe that this study has provided clear evidence that the
14 F. X. T. ET AL.
need for a structure-based drug design tool to find promis 3.7.1. Human pancreatic a-amylase with phytoconstitu
ing candidates for the drug development phase from natural ents of S. elaeagnifolium
sources has already been demonstrated. To identify the active antidiabetic molecules from the leaves
Similarly, to assess the antidiabetic potential of the chem of S. elaeagnifolium, nearly 26 ligands (23 phytochemicals
ical components identified by GC-MS in the S. elaeagnifolium and 3 diabetic drugs) were docked with the catalytic site of
leaves, the phytochemicals and drugs used for diabetics catalytic site of pancreatic alpha-amylase. Among the docked
were docked with diabetes-related proteins, such as pancre molecules, two metabolites of S. elaeagnifolium, cyclolaude
atic alpha-amylase, glycogen phosphorylase B, and phos nol and a-tocopherol, showed remarkable docking values
phorylase kinase. Among these, phytochemicals such as against pancreatic a-amylase. Interestingly, they were quite
a-tocopherol, cyclolaudenol, and campesterol were found to close to those of acarbose, glipizide, and metformin, and
be active antidiabetic candidates for all docked diabetic pro were even better (Table 5). The remaining phytochemicals
teins. Similar to the present study, the chemical constituents presented in Table 1 had negligible docking values, and
of chalcone, cinnamic acid, chlorogenic acid, ferulic acid, some also showed no interaction with the target. The results
kaempferol, naringin, rutin, salicylic acid, quercetin-3-o-beta- of this in silico study on the antidiabetic effects of plant
glucoside, and sinapic acid were detected by HPLC in the chemicals on pancreatic a-amylase are presented in Tables 1
leaves, flowers, and fruits of S. elaeagnifolium. Subsequently, and 2. According to this in silico screening, the two potent
the molecules were docked with type 2 diabetes protein phytochemicals found against alpha-amylase and antidiabetic
(Dipeptidyl Peptidase IV) to assess their inhibitory effect. In agents were described in terms of their docking scores, MM-
which, the rutin was found to be more effective with dock GBSA energies, and hydrogen contacts as follows.
ing scores of −8.10 kcal/mol, followed by quercetin-3-o-beta-
glucoside (-6.23 kcal/mol) and chalcone (-5.73 kcal/mol) 3.7.1.1. Cyclolaudenol. Cyclolaudenol had a notable docking
(Bouslamti et al., 2023). Based on their docking metrics (bind metric as a potential molecule for the inhibitors of human
ing affinities and docking scores) against dipeptidyl peptid pancreatic a-amylase, with docking scores of −7.94 kcal/mol
ase IV, they concluded that the aerial part of this plant could (Table 5) and an MM-GBSA energy of −41.847. Figure 8
have potent anti-diabetic properties due to its high concen shows the ligand-binding cavity of the human pancreatic
tration of polyphenolic chemicals. a-amylase. The evaluation of the interaction of this complex
In another research, the chemical components and some revealed that there were two hydrogen bonds (Figure 8).
other derivatives, namely astragalin, combretol, kaempferol, ASP197 and ARG195 were found to be the key residues
kaempferol 7-O-glucopyranoside, isorhamnetin 3-O-glucopyr responsible for their binding affinities with cyclolaudenol.
anoside, 30 -40 -50 -7-tetramethyl ether, and 5-hydroxy 3-7-40 -50 - Interestingly, these residues were found to covalently inter
tetramethoxyflavone-30-O-glucopyranoside were isolated act with this molecule. The hydrogen bond distances
from the leaves of S. stramonifolium (Dej-Adisai et al., 2022). between this complex were measured to be 1.61 Å for
Subsequently, the isolated molecules were subjected to in sil ASP197 and 2.70 Å for ARG195 (Figure 9a). In this case, the
ico antidiabetic research on a-glucosidase. All docked phyto residual contacts were connected to the hydroxyl (OH) group
chemicals were found to have strong binding affinities with of cyclolaudenol (Figure 9b).
the residues of a-glucosidase, making them possible antidia
betic agents (Dej-Adisai et al., 2022). In Indonesia, Solanum 3.7.1.2. a-Tocopherol. In the present study, a-tocopherol
torvum is known as takoka. Since the fruits of S. torvum are had modest docking scores (-7.41 kcal/mol) against human
consumed by diabetics, some of the phytoconstituents from pancreatic a-amylase enzyme (Table 5). However, it was
the seeds, such as methyl caffeate, phytol, neophytadiene, active against glycogen phosphosylase B. With docking
and hexadecenoic acid, were selected to study their inhibi scores of −7.41 kcal/mol, it was bound to the residues of this
tory effects on a-glucosidase enzymes using an in-silico diabetic target as hydrogen bonding and p-p stacking con
approach (Yulia Putri et al., 2022). In this molecular docking tacts (Table 5). This molecule has two contact lines: LYS200
study, methyl caffeate had a docking score of 6.90 kcal/mol. (hydrogen bond) and HIS201 (Pi-Pi stacking). The distance of
In addition, it has three contact lines with the a-glucosidase this contact was measured to be 2.02 Å (Figure 10a). It is also
residues. Based on their findings, we believe that this chem connected to the hydroxyl (OH) group of a-tocopherol
ical may have active properties in suppressing the enzyme (Figure 10b).
alpha-amylase, which is responsible for diabetes.
Furthermore, solanesol has been described as one of the 3.7.1.3. Standard drugs against human pancreatic
main components of Oxystelma esculentum R. Br (Francis a-amylase. In this study, acarbose, glipizide, and metformin
Xavier et al., 2022). It was also previously reported to be an were used as reference drugs to compare the docking met
active metabolite in amylase inhibition by in silico finding rics of the phytochemicals. Among the drugs, acarbose has
(Francis Xavier et al., 2022). However, the present GC-MS ana docking scores of −6.86 kcal/mol with MM-GBSA values of
lysis shows that it also occurs in the leaves of S. elaeagnifo −48.566 which is significantly lower than cyclolaudenol, cam
lium. In their in-silico study, solanesol showed minimal pesterol and Stigmasta-5,22-dien-3-ol and quite close to that
docking values and lower binding affinities towards the pro of a-tocopherol (Table 5). However, it has six hydrogen-
teins responsible for diabetes compared to tocopherol, cyclo bonding contacts with the residues of human pancreatic
laudenol and campesterol. alpha-amylase. In this case, all contacts were connected to
Table 5. The chemical constituents of S. elaeagnifolium as possible anti-diabetic agents for a-amylase.
S. Docking Scores
No Name of the Chemical constituent (kcal/mol) H-bond Contacts Other contacts
1 Cyclolaudenol −7.94 ASP197, ARG195 No interactions
2 a-Tocopherol −7.41 LYS200 HIS201 (Pi-Pi stacking)
3 Campesterol −7.36 GLU223 No interactions
4 Stigmasta-5, 22-dien-3-ol −7.08 No interactions ASP197, ASP300 (Salt bridge), TYR62 (Pi-cation),
TRP59 (Pi-Pi stacking)
5 Solanesol −7.07 HIS305 No interactions
6 a-amyrin −7.04 No interactions No interactions
7 c-sitosterol −6.64 GLU233 No interactions
8 Lycopersene −6.62 TYR151 No interactions
9 Betulin −6.62 GLN63, HIS305 No interactions
10 Geranyllinaloolisomerb −6.44 ASP300 No interactions
11 1-Pentacosanol −6.34 No interactions No interactions
12 1,2-Benzenedicarboxylicacid, diisooctylester −6.08 No interactions No interactions
13 Hexadecanoic acid, 2,3-dihydroxypropyl ester −6.07 GLU233 GLU233, ASP197, ASP300 (Salt bridge), TYR62
(Pi-cation)
14 M-Camphene −5.27 No interactions No interactions
15 Tetracosamethyl-Cyclododecasiloxane, −5.01 No interactions No interactions
16 Icosamethylcyclodecasiloxane −4.76 No interactions No interactions
17 Benzenemethanol −4.74 ASP197 TYR62 (Pi-Pi stacking)
18 Octadecamethyl-Cyclononasiloxane, −4.5 No interactions HIS G476(Pi-Pi stacking)
19 Tetradecamethyl-Cycloheptasiloxane, −4.31 No interactions No interactions
20 Hexadecamethyl-Cyclooctasiloxane, −4.16 No interactions No interactions
21 N, N-diethyl-Formamide, −3.73 No interactions No interactions
22 N, N-diethyl-Acetamide, −3.68 No interactions No interactions
23 1,2-benzenedicarboxylicacid, dibutylester 7.22 No interactions ASP300, GLU233, ASP197 Salt bridge, TYR62 (Pi-
cation)
Standard Drugs
24 Acarbose −6.86 ASP197, ARG195, GLU233, No interactions
GLY306, TYR151
25 Glipizide −6.11 THR163 No interactions
26 Metformin −3.11 ASP197, ASP300, GLU233 No interactions
glycogen phosphorylase B and was closer to or even better

than some standard drugs namely acarbose, metformin and
glipizide. The remaining phytochemicals shown in Table 6
had negligible docking values and no hydrogen bond inter
actions with the target residues. The results of this in silico
study on the antidiabetic effects of plant chemicals on glyco
gen phosphorylase B are presented in Table 6.
3.7.2.1. a-Tocopherol. Of the identified phytochemicals,

Figure 8. Active ligand binding pocket of human pancreatic alpha-amylase. a-tocopherol has docking scores of −7.91 kcal/mol and also
MM-GBSA values of −46.661 (Table 6), which are more sig
nificant than other phytochemicals including the reference
the hydroxyl groups of acarbose (Figure 11a). Furthermore, drug, CP-320626. It has one hydrogen bond with the target
glipizide has one hydrogen bond with the target residue. residue ASP339. The distance of this contact was measured
This contact was bound to the amine group of the glipizide to be 2.81 Å (Figure 13a). This contact was observed with the
(Figure 11b). Another antidiabetic drug, metformin, has six hydroxyl group (OH) of the a-tocopherol (Figure 13b).
contacts with residues ASP300, GLU233, and ASP197. Four
contacts were found to be hydrogen bonds and two were 3.7.2.2. Cyclolaudenol. Cyclolaudenol had the second-best
known as salt bridges. The binding affinities between these docking scores of −7.84 kcal/mol, close to those of a-tocoph
compounds were constructed using the amine groups of erol and even better than the reference ligands acarbose, gli
metformin (Figure 11c). pizide, metformin, and CP-320626 (Table 6). However, it has
one hydrogen bond with the catalytic site residue TYR 648.
The distance of this contact was measured to be 1.84 Å
3.7.2. Glycogen phosphorylase B with phytoconstituents (Figure 14a). It is also connected to the hydroxyl (OH) group
of S. elaeagnifolium of a-tocopherol (Figure 14b).
There were 27 ligands (23 phytochemicals and 4 reference
drugs), including CP-320626, which were docked with the 3.7.2.3. Standard drugs against glycogen phosphorylase
catalytic site of catalytic site of glycogen phosphorylase B B. The reference molecules had moderate docking scores
(Figure 12). Among the docked molecules, a-tocopherol among the docked molecules that are presented in Table 6.
showed a remarkable docking score (-7.21 kcal/mol) against However, compared with a-tocopherol and cyclolaudenol,
16 F. X. T. ET AL.
Figure 9. Cyclolaudenol: a). residues and hydrogen bond contacts with their distance values with 1B2Y protein and b). the 2D template shows the sort of interac
tions that exist between the hydroxy groups of cyclolaudenol with human pancreatic alpha-amylase.
Figure 10. a-Tochopherol: a). residues and hydrogen bond contacts with their distance values with 1B2Y protein and b). the 2D template shows the sort of interac
tions that exist between the hydroxy groups of a-Tochopherol with human pancreatic alpha-amylase.
they had negligible docking values. Assessment of binding Interestingly, all these hydrogen bonding contacts were asso
affinities showed that all molecules had significant binding ciated with the hydroxyl groups of acarbose. Metformin
affinities for glycogen phosphorylase B residues (Table 6). forms three hydrogen bonds with ASP339 and ALA383. In
The reference molecule of glycogen phosphorylase B, namely particular, ALA383 was found to form a covalent hydrogen
CP-320626 had docking values (-7.21 kcal/mol) close to those bond with the amine group of metformin (Figure 15c).
of a-tocopherol and cyclolaudenol; whereas it has similar Another antidiabetic drug, glipizide, has six contacts, four of
binding affinities as phytochemicals. The oxygen group of which are hydrogen bonds, two of which are known to be
this molecule has two hydrogen bond contacts with residues pi-cation and pi-pi stacking contacts (Figure 15d).
ARG569 and LYS574, whereas a p-p stacking contact was
also found between this complex (Figure 15a). CP-320626 is
a unique molecule for this target that has been deposited in 3.7.3. Phosphorylase kinase with phytoconstituents of S.
a protein database together with glucose in complex form elaeagnifolium
with glycogen phosphorylase B (Oikonomakos, 2002). It has The identified 26 ligands (23 phytochemicals and 3 diabetic
been previously described as an effective antidiabetic agent drugs) were docked with the catalytic site of catalytic site of
because it inhibits liver glycogen phosphorylase without phosphorylase kinase. Among the docked molecules, two
altering plasma insulin levels in diabetic mice. Another in sil metabolites of S. elaeagnifolium, a-tocopherol and campes
ico study revealed that it is also an effective anti-diabetic terol, showed notable docking scores of −7.25 kcal/mol and
agent against muscle glycogen phosphorylase B, as it has a −6.96 kcal/mol against phosphorylase kinase. Interestingly,
strong affinity with glycogen phosphorylase B (Oikonomakos, they are quite close to those of acarbose, glipizide, and met
2002). Acarbose has five hydrogen bond contacts. It had formin and are even better. The remaining phytochemicals,
strong binding affinities with the following residues: TYR90, shown in Table 1, had negligible docking values and did not
GLY675, GLY134, ASP283, and ASP 284 (Figure 15b). interact with the target. The results of this in silico study on
Figure 11. The 2D template shows the sort of interactions that exist between the functional groups of reference drugs with human pancreatic alpha-amylase.
evaluation of the interaction of this complex revealed that

there were two hydrogen bonds (Figure 16a). MET106 and
ASP104 were found to be the key residues responsible for
their binding affinities with a-tocopherol. The interaction dis
tances were measured to be 2.25 Å for MET106 and 2.22 Å
for ASP104 (Figure 16a). In this case, residual contacts were
connected to the hydroxyl (OH) group of a-tocopherol
(Figure 16b).
3.7.3.2. Campesterol. Campesterol had a docking score of

−6.96 kcal/mol among the docked ligands (Table 7). There
was a hydrogen bond contact with ASP167 at a distance of
1.52 Å (Figure 17a). It bound well with the hydroxyl group
(OH) of campesterol (Figure 17b).
Figure 12. Active ligand binding pocket of glycogen phosphorylase B. 3.7.3.3. Standard drugs against phosphorylase kinase. The
standard drugs, such as acarbose, metformin, and glipizide,
exhibited moderate docking values among the docked mole
the antidiabetic effects of the identified phytochemicals cules, as presented in Table 7. However, compared with
against phosphorylase kinase are presented in Tables 1 and a-tocopherol, campesterol and cyclolaudenol had negligible
2. According to this in silico screening, two potent phyto docking values (Table 7). Acarbose has six hydrogen-bond
chemicals were found against phosphorylase kinase, which contacts (Figure 18a). Four contacts were found as hydrogen
were described in terms of their docking scores, MM-GBSA bonds, and two were found as salt-bridge contacts with the
energies, and hydrogen contacts as follows. following residues: ASP167, GLU110, and ASP 113.
Interestingly, residue ASP113 strongly bound to the hydroxyl
3.7.3.1. a-Tocopherol. The compound, a-tocopherol had a and ammonia groups of acarbose. Furthermore, metformin
notable docking metrics as a potential molecule for phos had five contacts with the target (Figure 18b). Four contacts
phorylase kinase where it has docking scores of −7.25 kcal/ were found as hydrogen bonds, and one was found as a salt
mol with a MM-GBSA energy of −57.632 (Table 7). The bridge contact with the following residues: GLU110 and
18 F. X. T. ET AL.
Table 6. The chemical constituents of S. elaeagnifolium as possible anti-diabetic agents for glycogen phosphorylase B.
S. Docking Scores
No Name of the Chemical constituent (kcal/mol) H-bond Contacts Other contacts
1 a-Tocopherol −7.91 ASN282 No interactions
2 Cyclolaudenol −7.84 TYR648 No interactions
3 Stigmasta-5, 22-dien-3-ol −7.76 TYR648 GLU672 (Salt bridge)
4 c-sitosterol −6.70 No interactions No interactions
5 Betulin −6.20 No interactions No interactions
6 Benzenemethanol −5.42 ASN284 ARG292 (pi-cation), HIS341 (pi-cation),
7 Campesterol −5.02 No interactions No interactions
8 Lycopersene −4.82 No interactions GLU385 (Salt bridge)
12 Solanesol −4.05 GLU40 GLU233 (Salt bridge), ASP300 (Salt bridge),
ASP197 (Salt bridge) and TY62 (pi-cation),
14 Hexadecanoic acid, 2,3-dihydroxypropyl ester −3.94 GLU385 GLU385 (Salt bridge), HIS341 (pi-cation),
15 a-amyrin −3.80 No interactions No interactions
16 1,2-benzenedicarboxylicacid, dibutylester −3.49 No interactions GLU385 (Salt bridge)
17 Geranyllinaloolisomerb −2.09 SER674 No interactions
19 1-Pentacosanol −1.90 No interactions No interactions
20 Octadecamethyl-Cyclononasiloxane, −1.88 No interactions No interactions
23 1,2-Benzenedicarboxylicacid, diisooctylester −1.00 No interactions No interactions
Standard drugs
24 CP-320626 −7.21 GLY306, HIS305 TRP59 (Pi-Pi stacking)
25 Acarbose −6.86 ASP283, ASN284, GLY134, No interactions
GLY675, TYR90
26 Metformin −4.70 ASP339, ALA383, HIP341 No interactions
27 Glipizide −3.53 GLY677, THR676, LYS568 LYS680 (Salt bridge), LYS574 (Pi-cation), HIP341
(Pi-Pi stacking)
Figure 13. a-Tochopherol: a). residues and hydrogen bond contacts with their distance values with glycogen phosphorylase B protein and b). The 2D template
shows the sort of interactions that exist between the hydroxy groups of a-Tochopherol with glycogen phosphorylase B.
LEU110. As evidence of strong binding affinities, these two clots. It also helps reduce cell damage triggered by oxidative
residues were covalently and trivalently linked to the amino stress and is currently being researched as a preventive and
group of metformin. Another antidiabetic drug, glipizide, controlling agent for some cancers (https://atbcstudy.cancer.
forms three hydrogen bonds with the following residues: gov/). Campesterol also has a cholesterol-lowering, anti-
VAL29, LYS151, and GLU110. In this case, the binding affin carcinogenic and anti-inflammatory effect (Data Sheet:
ities between these compounds were determined using both Cat.No. T4S2157).
the oxygen and ammonia groups of glipizide (Figure 18c).
3.9. Molecular dynamic simulations

3. 8. Therapeutic effects of a-tocopherol and
Phytochemicals identified as antidiabetic agents by molecular
campesterol
docking were chosen for MD simulations to explore their sta
Generally, a-tocopherol, also known as vitamin E, strengthens bility and residue fluactuation within the catalytic site of the
the immune system and aids in the prevention of blood targets. In this context, we evaluated the root mean square
Figure 14. Cyclolaudenol: a). residues and hydrogen bond contacts with their distance values with glycogen phosphorylase B protein and b). the 2D template
shows the sort of interactions that exist between the hydroxy groups of cyclolaudenol with glycogen phosphorylase B.
Figure 15. The 2D template shows the sort of interactions that exist between the functional groups of reference ligands with glycogen phosphorylase B.
20 F. X. T. ET AL.
Table 7. The chemical constituents of S. elaeagnifolium as possible anti-diabetic agents for phosphorylase kinase.
S. No Name of the Chemical constituent Docking Scores (kcal/mol) H-bond Contacts Other contacts
1 a-Tocopherol −7.25 ASP104, MET106 No interactions
2 Campesterol −6.96 ASP167 No interactions
3 Gamma-sitosterol −4.17 No interactions No interactions
4 Solanesol −4.11 GLU110 GLU110 (Salt bridge)
5 Stigmasta-5, 22-dien-3-ol −5.14 MET106 ASP167 (Salt bridge)
6 Lycopersene −3.98 No interactions GLU110 (Salt bridge), PHE103 (Pi-cation)
7 a-amyrin −3.94 THR166 No interactions
8 Cyclolaudenol −3.65 No interactions No interactions
9 Betulin −3.07 ASP167 No interactions
10 1-Pentacosanol −2.67 No interactions ASP176 (Salt bridge)
11 Geranyllinaloolisomerb −2.44 MET E106 No interactions
12 1,2-benzenedicarboxylicacid, dibutylester −2.20 No interactions ASP167 (Salt bridge)
13 Hexadecanoic acid, 2,3-dihydroxypropyl ester −1.55 THR166 ASP167 (Salt bridge), PHE103 (Pi-cation)
14 Octadecamethyl-Cyclononasiloxane, −1.39 No interactions No interactions
15 1,2-Benzenedicarboxylicacid, diisooctylester −114 No interactions No interactions
21 Benzenemethanol −1.01 MET106 No interactions
Standard Drugs
24 Glipizide −4.53 GLU110, LYS151, VAL29 No interactions
25 Acarbose −5.16 ASP167, ASP113, GLU110 ASP113, GLU110 Salt bridge
26 Metformin −3.00 GLU110, LEU25 GLU110 (Salt bridge)
Figure 16. a-Tochopherol: a). residues and hydrogen bond contacts with their distance values with glycogen phosphorylase B protein and b). the 2D template
shows the sort of interactions that exist between the hydroxy groups of a-Tochopherol with phosphorylase kinase.
Figure 17. Campesterol a). residues and hydrogen bond contacts with their distance values with glycogen phosphorylase B protein and b). the 2D template shows
the sort of interactions that exist between the hydroxy groups of campesterol with phosphorylase kinase.
Figure 18. The 2D template shows the sort of interactions that exist between the functional groups of reference drugs with phosphorylase kinase.
Figure 19. Molecular dynamics simulation of the complex cyclolaudenol and human pancreatic alpha-amylase: a. Root Mean Square Deviation (RMSD), b. Root Mean Square
Fluctuation (RMSF), c). protein-ligand contacts shows the H-bond occupancy throughout the trajectory for cyclolaudenol d). ligand Root Mean Square Fluctuation (L-RMSF).
22 F. X. T. ET AL.
deviation (RMSD), root mean square deviation (RMSF), pro and the human pancreatic alpha-amylase complex provides
tein-ligand interactions, and L-RMSF. The RMSD represents valuable insight into the interaction between ligand atoms
the average displacement of a group of atoms relative to a and the protein and shows the entropic contributions they
reference frame within a given frame. make to the binding process. The “Ligand fit on Protein” line
graph illustrates how the ligand fluctuates relative to the
protein (Figure 19d). First, the protein-ligand complex was
3.9.1. Human pancreatic alpha-amylase complex aligned with the protein backbone, and then the RMSF for
In the MD simulations, the cyclolaudenol-human pancreatic the heavy ligand atoms was measured. The RMSD of a-toc
alpha-amylase complex reached equilibrium after 37 ns opherol and human pancreatic alpha-amylase complex
(Figure 19a). Equilibrium was maintained up to a 100 ns tra reached equilibrium after 60 ns (Figure 20a). Equilibrium was
jectory with minimum and maximum values of 0.5 and maintained up to a 100 ns trajectory with minimum and
1.63 Å, respectively. The Ca atoms reached a uniform fluctu maximum values of 0.58 and 3.80 Å. Furthermore, the green
ation from 0.2 Å, and lasted up to100ns (Figure 19a). The vertical lines in the plot show the residues of human pancre
RMSF plots illustrate the protein regions, particularly the N- atic alpha-amylase that contribute to interactions with a-toc
and C-termini, which exhibited the highest degrees of fluctu opherol (Figure 20b). Figure 20c shows the occupancy of
ation during the simulation. In addition, the green vertical hydrogen bonds between a-tocopherol and human pancre
lines in the plot show the residues of human pancreatic atic alpha-amylase residues along the trajectory. The L-RMSF
alpha-amylase that contribute to interactions with cyclolau plot of a-tocopherol and the human pancreatic alpha-amyl
denol. Figure 19b shows the occupancy of the hydrogen ase complex provides valuable insights into the interaction
bonds between cyclolaudenol and human pancreatic alpha- between ligand atoms and the protein (Figure 20d).
amylase residues along the trajectory (Figure 19c). The occu Conversely, the root means square deviation (RMSD) of the
pancy of this interaction was monitored continuously acarbose and human pancreatic alpha-amylase complex
throughout the simulation. The L-RMSF plot of cyclolaudenol exhibited gradual fluctuations until the end of the simulation
Figure 20. Molecular dynamics simulation of the complex a-tocopherol and human pancreatic alpha-amylase: a. Root Mean Square Deviation (RMSD), b. Root
Mean Square Fluctuation (RMSF), c). protein-ligand contacts shows the H-bond occupancy throughout the trajectory for a-tocopherol d). ligand Root Mean Square
Fluctuation (L-RMSF).
Figure 21. Molecular dynamics simulation of the complex acarbose with human pancreatic alpha-amylase: a. Root Mean Square Deviation (RMSD), b. Root Mean
Square Fluctuation (RMSF), c). protein-ligand contacts shows the H-bond occupancy throughout the trajectory for acarbose d). ligand Root Mean Square
Fluctuation (L-RMSF).
(Figure 21a). Figure 21b shows that the diabetic protein resi glycogen phosphorylase B showed that RMSD had better sta
dues had a strong hydrogen bonding contact with acarbose, bility at 63–100 ns. No significant fluctuations were observed
which is shown as green vertical lines. Figure 21c shows the between 10 and 60 ns (Figure 23a). Figure 23b shows that
occupancy of hydrogen bonds between acarbose and human the diabetic protein residues have strong hydrogen bonding
pancreatic alpha-amylase residues along the trajectory. On contact with glipizide, which is shown as green vertical lines.
the other hand, The L-RMSF plot of acarbose and the human Figure 23c shows the occupancy of the residues in various
pancreatic alpha-amylase complex provides valuable insights hydrogen-bond contacts with the ligand. Figure 23d shows
into the interaction between ligand atoms and the protein the fluctuation of the glipizide atoms during the simulations.
(Figure 21d). Previously, the chemical constituent quercetin-3-O-beta-glu
coside was isolated from S. elaeagnifolium and identified as a
potent inhibitor of a-amylase through in silico research.
3.9.2. Glycogen phosphorylase B complex Based on docking metrics, MD simulations were performed
The complex of a-tocopherol and glycogen phosphorylase B for 200 ns (Basnet et al., 2022). However, the MD simulation
showed that the RMSD at 27 ns and 80 ns had better stabil showed that a-amylase was unstable throughout the stimula
ity, whereas a slight fluctuation between the ligand and pro tion, according to the ligand-protein interaction diagram
tein was detected throughout the entire trajectory, except (Basnet et al., 2022). Another study documented that the
for 27 ns and 80 ns (Figure 22a). Figure 22b shows that the complex of hexadecenoic acid and a-amylase had an energy
diabetic protein residues have strong hydrogen bonding difference at 40 ns and after 80 ns in the period of 100 ns.
contact with a-tocopherol, which is shown as green vertical After 70 ns, a stabilized energy of <Å is observed in this
lines. Figure 22c shows the occupancy of the residues in vari complex. The RMSF plot reveals residue fluctuations. Based
ous hydrogen-bond contacts with the ligand. Figure 22d on their findings, they documented that hexadecenoic acid
shows the fluctuation in the a-tocopherol atom during the has remarkable effects and acts as an antidiabetic agent in
simulations. Ultimately, the complex of glipizide and type 2 diabetes mellitus (Renganathan et al., 2021).
24 F. X. T. ET AL.
Figure 22. Molecular dynamics simulations of the complex a-tocopherol and glycogen phosphorylase B: a. Root Mean Square Deviation (RMSD), b. Root Mean Square
Fluctuation (RMSF), c). protein-ligand contacts shows the H-bond occupancy throughout the trajectory for a-tocopherol d). ligand Root Mean Square Fluctuation (L-RMSF).
Figure 23. Molecular dynamics simulation of the complex glipicide and glycogen phosphorylase B: a. Root Mean Square Deviation (RMSD), b. Root Mean Square
Fluctuation (RMSF), c). protein-ligand contacts, d). ligand Root Mean Square Fluctuation (L-RMSF).
Comparing these two data, the phytochemicals cyclolaude References

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Phytochemical composition, anti-microbial, anti-oxidant and anti-diabetic effects

ABSTRACT ARTICLE HISTORY

1. Introduction therapeutics against cancer, diabetes, the central nervous

Figure 1. Sources of reactive oxidative stress that cause cell lysis.

2.7.2. Inhibitory assay of a-glucosidase

Figure 2. Residues of human pancreatic alpha-amylase (PDB ID: 1B2Y).

Figure 3. Residues of glycogen phosphorylase B (PDB ID: 1B2Y).

Table 2. Total antioxidant activity of S. elaeagnifolium leaf extracts.

Table 3. Antibacterial activity of S. elaeagnifolium leaf extracts by minimum inhibitory concentration.

3.6. GC–MS detected phytochemicals of Solanum kaempferol, rutin, quercetin-3-O-beta-glucoside, quercetin,

Figure 6. GC-MS peak areas of the ethanol extracts of S. elaeagnifolium.

Table 4. GC-MS analysis of S. elaeagnifolium ethanol leaf extract.

glycogen phosphorylase B and was closer to or even better

3.7.2.1. a-Tocopherol. Of the identified phytochemicals,

evaluation of the interaction of this complex revealed that

3.7.3.2. Campesterol. Campesterol had a docking score of

3.9. Molecular dynamic simulations

Comparing these two data, the phytochemicals cyclolaude­ References

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Comparing these two data, the phytochemicals cyclolaude References