Molecular Docking and ADME-Toxicity Studies of Potential

Compounds of Medicinal Plants Grown In Indonesia as An

Anti-rheumatoid Arthritis
Rizki Awaluddin1,a), Wildan Khairi Muhtadi2,b), Lutfi Chabib1,3,c), Zullies Ikawati3,d)
, Ronny Martien3,e), Hilda Ismail3,f)
1
Pharmacy Departement, Universitas Islam Indonesia, Yogyakarta, 55584, Indonesia.
2
Professional Pharmacy Education Program, Pharmacy Departement, Universitas Islam Indonesia, Yogyakarta,
55584, Indonesia
3
Faculty of Pharmacy,Gadjah Mada University, Yogyakarta, 55281, Indonesia

Corresponding author: c)lutfi.chabib@uii.ac.id; a)awaluddinrizki@gmail.com; b)muhtadiwildan@gmail.com;

d)
ikawati@yahoo.com; e)martien_ronny@yahoo.com; f)hilda_fa@ugm.ac.id

Abstract. Rheumatoid arthritis (RA) is an autoimmune disease with recurrent bone destruction around the joints that
could lead to permanent joint damage. DMARDs (Disease Modifying Anti-Rheumatoid Drugs) and NSAIDs (Non-
Steroid Anti-Inflammatory Drugs) are the RA therapies with many side effects on long term use. Based on the
ethnomedicine, there are many plants that could be found in Indonesia that contain the potential compounds as alternative
RA therapies. The aim of this study is to assess the potential of compounds of various medicinal plants against multiple
proteins that play an important role on RA through the molecular docking study and pharmacokinetic prediction.
Hesperidin, EGCG (Epigallocatechin gallate), and mangiferin showed higher activity compared to the other compounds
against TACE (TNF-α converting enzyme) which play an important role in the inhibition of TNF-α. Inhibition on it could
suppress macrophage cell and T-cell activity by suppressing the regulation of cytokine secretion against inflammation.
Furthermore, hesperidin, EGCG, and mangiferin did not show effects on CYP450 (cytochrome P450). Modification of
drug delivery system must be done to increase the bioavailability of the compounds. It can be concluded that hesperidin,
EGCG, and mangiferin are potential to be developed as an RA therapy with a modification of drug delivery system. This
study suggest the encapsulation method using liposome as the drug carrier, which is suitable with the charactheristic of
hesperidine, EGCG, and mangiferin.

INTRODUCTION
Rheumatoid arthritis (RA) is a chronic autoimmune disease with symptoms of pain and stiffness of joints that
occur progressively that may lead to permanent disability [1]. It is characterized by chronic inflammation of the
synovium, erosion of the articular cartilage that occurs progressively, and destruction of joints [2]. The pathogenesis
of RA is greatly influenced by many cytokines, which are synthesized during the immune response. Uncontrolled
production of pro-inflammatory cytokines, such as Tumor necrosis factor-alpha (TNF-α), Interleukin-1 (IL-1), and
Interleukin-6 (IL-6) may generate autoimmunity [3].
TNF-α is one of the main cytokines that plays a significant role in RA. It is a pro-inflammatory cytokine that is
produced not only by activated macrophages but also by monocytes, fibroblasts, mast cells and NK cells [4]. TNF-α
has an ability to induce a variety of signaling pathways of the immune system and responsible for the tissue
inflammation. An inhibition of TNF-α would suppress the function of macrophages and T-cells, and reduce the
development of inflammation as well [5][6]. TNF-α also generates the production of other pro-inflammatory
cytokines such as IL-1 and IL-6. IL-1 has 11 families, which are responsible for the regulation of immunity, and also
involved to the proliferation of B-cells and T-cells. IL-1β, which is one of the IL-1 family is the main cytokine

International Conference on Chemistry, Chemical Process and Engineering (IC3PE) 2017

AIP Conf. Proc. 1823, 020033-1–020033-9; doi: 10.1063/1.4978106
Published by AIP Publishing. 978-0-7354-1491-4/$30.00

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which stimulates the expression of COX-2 during inflammation [7-8]. High concentration of IL-1β in plasma and
synovial fluid has been found involved in many cases to the duration of morning stiffness in RA patients. IL-6 has
also been found at a high level in the blood and synovial fluid of RA patients. IL-6 has an activity on neutrophils
that secretes reactive oxygen intermediates and proteolytic enzymes, which lead to inflammation and joint
destruction [4]. In the previous study, the activation of TNF- α and IL-1β receptor has been found related to the
production of pro-inflammatory cytokines that were regulated by the activity of p38 Mitogen Activated Protein
Kinase (MAPK), Extracellular signal-Regulated Kinases (ERK), Protein Kinase C (PKC), Nuclear Factor Kappa B
(NF-kB), and the other enzymes [9].
Based on the ethnomedicine, there are many plants that grow in Indonesia that contain the potential compounds
with an activity as the treatment of RA. Many experiments have also been conducted to examine the activity of the
potential compounds. It is expected to be an alternative of DMARDs (Disease Modifying Anti-Rheumatoid Drugs)
such as methotrexate (MTX) and NSAIDs (Non-Steroid Anti-Inflammatory Drugs), which are the drugs that widely
used as main therapy in RA patients. Molecular docking of many potential compounds that are contained in many
plants is conducted in this study to examine their activity of cytokine inhibitory mechanism against multiple protein
targets in the patient with RA. The ADME-toxicity prediction is conducted to examine the profile of absorption,
distribution, metabolism, excretion and toxicity of the potential compounds. The model of Drug Delivery Systems
(DDS) is also provided in this study to suggest the best DDS that could be used to deliver the potential compounds
to their target of action.
TABLE 1. Traditional medicinal plants as the therapy of RA
Part of the plants/Extraction
Indonesian name of plants Bioactive compound
method
Brotowali
Stem/ aqueous extract Berberine (Alkaloid)
(Tinospora cordifolia)
Cabai
Fruit Capsaicin (Alkaloid)
(Capsicum annum)
Aloe Vera
Leaf Cinnamic acid
(Aloe barbadensis)
Kunyit
Rhizome Curcumin (Polyphenol)
(Curcuma longa)
Jahe
Rhizome Gingerdiol
(ZIngiber officinale)
Teh Epigallocatechin gallate (EGCG)
Leaf/ maceration with etanol
(Camellia sinensis) and Catechin (Tannin)
Jeruk Purut
Leaf Hesperidin (Flavanone)
(Rosmarinus officinalis)
Mangga Young leaf/ methanol extract with
Mangiferin (Xanthonoid)
(Mangifera indica) soxhlet apparatus
Merica
Fruit/ soxhlet with ethanol Piperine (Alkaloid)
(Piper nigrum)
Bawang Merah
Fruit Quercetin (Flavonol)
(Allium cepa)

MATERIALS AND METHODS

Materials
The structure of eleven potential compounds, which are berberine, capsaicin, catechin, cinnamic acid, curcumin,
epigallocatechin gallate (EGCG), gingerdiol, hesperidin, mangiferin, piperine, quercetin, and Methotrexate (MTX)
as the comparative drug compound were designed using Marvin Sketch (ChemAxon). The ligands were made using
MDL MOL format (.mol).
The macromolecular proteins that mediate inflammation in Rheumatoid Arthritis (RA) were downloaded from
the database of Protein Data Bank (http://www.rcsb.org) [10]. The codes of macromolecular proteins that were used
are MAPK14 (1YW2), TACE (3KME), IRAK4 (4RMZ), ICE (3NS7), NF-Kb (4KIK), ERK (2OJI), PKC (1XJD),

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COX2 (6COX), and COX1 (1EQG). The selected target proteins had native ligand and were validated by measuring
the Root Mean Square Deviation (RMSD) values that were <2.0 Å.
The softwares that were used in this study are Marvin Sketch (ChemAxon: Academic License), iGemDock v2.4
(BioXGEM: Open Source), Chimera (UCSF: Academic License).

Methods
Molecular Docking and Visualization

The examination of ligand compound activity against a receptor was conducted using iGemDock v2.4, with a
concordance between the size of binding site with the result of protein validation. The result of docking score was
presented in the fitness Score on Post Screening Analysis. Screening analysis was conducted with the population
size of 300, generation of 80, and 3 resulting solutions.

ADME-Toxicity Prediction

The pharmacokinetic profile prediction of eleven potential compounds was conducted using ADMETSAR server
(http://lmmd.ecust.edu.cn:8000/predict/) [11], which included prediction of absorption, metabolism, distribution,
excretion, and toxicity of the potential compounds.

RESULTS AND DISCUSSION

Molecular docking study

A binding site is required to know the interaction between ligand and macromolecule. The RMSD describes the
ability of binding site in a macromolecule to settle a ligand that possesses the lowest energy at a position that close
to the real position. The RMSD value >2Å indicates inaccurate docking position in the binding site. TABLE 2
indicated that the RMSD value of 3NS7 protein should be considered due to its value of RMSD >2Å.
Molecular docking assumes that a compound is absorbed perfectly and interacted with the receptor. The lowest
docking energy indicates the most significant interaction between ligand and receptor. The previous study reports
that twelve ligands that are tested in this study have the effect as an anti-inflammation in the therapy of RA. The
ligands were tested on various receptors that related with TNF-α, Interleukin-β, Kinase, and cyclooxygenase, which
are the main receptors that mediate RA.
TABLE 2. Result of protein target validation as RMSD value
1YW2 3KME 4RMZ 3NS7 4KIK 2OJI 1XJD 6COX 1EQG
1.049 0.433 1.053 2.17 0.979 1.673 1.089 1.513 1.270

FIGURE 1. Molecular docking of various potential compounds

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 TABLE 3. Interaction profiles of the potential compounds on TNF-α Converting Enzyme (TACE)
No Compound Name Energy (Kcal/mol) Van Der Walls H-Bond Electrostatic
1 Hesperidin -171.042 -116.179 -54.8623 0
2 Mangiferin -155.920 -106.575 -49.3451 0
3 EGCG -151.783 -109.156 -42.6275 0
4 Methotrexate -147.799 -111.885 -26.5761 -9.34
5 Quercetin -133.544 -105.178 -28.366 0
6 Catechin -128.952 -109.238 -19.7136 0
7 Capsaicin -123.775 -103.522 -20.2527 0
8 Gingerdiols -123.483 -101.393 -22.0905 0
9 Curcumin -117.556 -97.8446 -19.7112 0
10 Berberine -102.046 -95.9833 -6.06272 0
11 Piperine -101.501 -98.314 -3.18686 0
12 Cinnamat Acid -86.6389 -70.3662 -12.867 -3.40
13 Salicilic Acid -83.7612 -59.3325 -18.9978 -5.43

The result of docking showed in FIGURE 1 indicated that TACE enzyme was the receptor with the lowest
energy that occupied by all ligands. The enzyme that occupied by ligand with the lowest energy indicates the most
comfortable condition or position of ligand in a receptor that could generate a pharmacological effect. The analysis
of docking result needs various parameters of identification to describe the ligand interaction. iGemDock identifies
various bond energies, such as hydrogen bond (H-Bond), Van Der Walls (VDW) interaction, and electrostatic (Dock
Energy= H-Bond Energy + VDW Energy + Electrostatic Energy), which are the interactions that occur between
ligand and receptor. The H-Bond interaction in ligand is related to the interaction of the hydrophilic group or the
presence of atom with lone pair electron, while the VDW interaction is related to lipophilic groups such as aromatic
ring, or metil group such as piperine that contains aromatic group and carbon chain so that piperin possesses lower
VDW energy than H-Bond energy. Hesperidin and mangiferin possess hydrophilic group in the form of hydroxy that
indicates lower H-Bond energy than VDW energy. TABLE 3 indicated that EGCG, Hesperidin, and Mangiferin
possessed lowest docking energy, which were respectively -151.783, -171.042, and -155.92. The docking energy
that is shown in TABLE 3 was the combination of van der walls energy, hydrogen bond, and electrostatic that was
the result of the interaction between ligands and macromolecules. The docking energy is also represented by
FIGURE 2, which showed the dock pose in the TACE protein.

FIGURE 2. Dock pose of EGCG (purple), hesperidin (brown), and mangiferin (green) on TACE
TACE is a membrane-linked enzyme that contains two domains, which are disintegrin and matrix
metalloproteinase. The enzyme plays a significant role in the regulation of membrane-linked proteins, such as TNF-

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α, Fas ligand, TNF receptor, and growth factor receptor. TACE works by regulating the TNF-α production pathway
that converts Pro-TNF-α into an active form as TNF-α that would be bonded with the receptor of TNFR1 (p55) and
TNFR2 (p75). Although both of them have the same structure and function, they have a difference in the signal
transduction, with the main characteristic is the presence of death domain that could be found only in TNFR1 as the
inducer of cellular apoptosis that causes inflammation [12-13].
In this study, curcumin indicated lower activity compared to MTX and the best potential compounds (EGCG,
mangiferin, and hesperidin). Nevertheless, a study conducted by Ikawati found that the dosage of 80 mg/kg of
gamavuton (GVT-0), which is an analog of curcumin, possessed better ability to lower the arthritis index compared
to MTX [2]. Furthermore, GVT-0 possesses lower toxicity and lower influence to CYP450 enzyme compared to
curcumin. GVT-0 also possesses a specific inhibition activity against TACE and ICE enzymes.[14]
In the previous study, it has been reported that dosage of 160 mg/kg Hesperidin could reduce both level of TNF-
α and bone tissue destruction compared to 150 mg/kg of Chloroquine as the standard [15]. Hesperidin has also been
reported to possess the activity of anti-inflammation in the percentage of 62,86% at the dosage of 300 mg/kg against
the treatment of 20 mg/kg diclofenac [16].
The anti-inflammation activity of Mangiferin and EGCG have also been reported in the previous study. The pre-
clinical study that has been conducted by another researcher indicates that 100 mg/kg of Mangiferin is able to
lowering the level of cytokines (TNF-α, IL-β, RANKL, and IL-6) significantly on the CIA (Collagen-Induced
Arthritis) mice against the negative control [17]. Syarayah reports that EGCG as an antioxidant works by lowering
the phosphorylation of IkB to block the IL-1β that is induced by the activation of NF-kB. Mota reports that 140
mg/kg of EGCG shows a decrease of the expansion of cell inflammation in the mice that have been induced with
inflammation [18].

FIGURE 3. Mechanism of Inflammation on TACE Pathway [12]

ADME-Toxicity prediction
The evaluation of ADMET is required to predict the pharmacokinetic profile of the potential compounds. The
physicochemical properties of a compound determine the bioavailability of a compound in the body.
Pharmacokinetic identification of a drug consists of identification of absorption, distribution, metabolism, excretion,

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and toxicity. Absorption of a compound is influenced by some factors, such as lipophilicity, hydrogen bonds,
molecule size, and pKa charge [19].
Mangiferin, EGCG, and Hesperidin showed the optimal pharmacological activity compared to the other
compounds. However, all of them indicated low permeability to pass the stage of membrane absorption. Based on
TABLE 1, Mangiferin, EGCG, and Hesperidin tended to be hydrophilic, which mean they would have low
bioavailability in plasma. Therefore, they would be able to be delivered to their target of action site using the
intravascular Drug Delivery System (DDS), which could increase their bioavailability in plasma. A modification of
DDS is necessary to be conducted to overcome an uncomfortable experience arising from intravascular drug
delivery and also to increase the bioavailability of Mangiferin, EGCG, and Hesperidin.
At the metabolism stage, as shown in TABLE 3, some compounds (3, 4, and 6-10) did not influence the activity
of Cytochrome P450 (CYP450) enzymes, especially for mangiferin, EGCG, and hesperidin. The activity of the
compound that influences CYP450 enzymes would accelerate or prolong the process of metabolism of a compound.
Toxicity of the compounds, as shown in the TABLE 4, was identified based on the reactivity of compounds against
body tissues, such as the parameter of acute toxicity, carcinogenic, and xenobiotic potency. EGCG and mangiferin
possessed higher toxicity level that was categorized as High Toxic compared with hesperidin, whereas MTX as the
conventional therapy of RA is categorized as Low Toxic. Therefore, it is necessary to conduct the monitoring of
toxicity in the use of EGCG, mangiferin, and hesperidin as the lead compounds.
So that in this study, the three potential compounds, which are EGCG, mangiferin, and hesperidin possess the
cytokine inhibition activity in the inflammation pathway of RA, marked by the lowest docking energy against
various cytokine receptors. TACE is one of the receptors that plays an important role in the inflammation
mechanism of RA. The interaction that occurs between the receptor of TNF-α and the active form of TNF-α that
modified by TACE will generate an inflammation. The inhibition of TACE is suspected as the main pathway of the
RA therapy, although the other inhibition mechanism also plays an important role.
TABLE 4. Absorption profile of the potential compounds
Parameter 1 2 3 4 5 6 7 8 9 10 11 12
BBB + + - + + - + - - - + -
Human Intestinal
- + + + + + + + + + + +
Absorption
Caco-2
+ + - + + - + - - - + -
Permeability
Permeability
1.23 1.16 -0.52 1.89 0.65 -0.86 0.75 -0.41 -0.28 -0.36 1.41 -0.22
(cm/s)
P-glycoprotein
NS S S NS S S S S S S S S
substrate
P-glycoprotein
NI NI NI NI I NI NI NI NI NI NI NI
inhibitor
Renal organic
I NI NI NI NI NI NI NI NI NI I NI
cation transporter
LogP 3.6 3.6 0.4 2.1 3.2 1.2 3 -1.1 -0.4 -1.8 3.5 1.5
TPSA (Å) 40.8 58.6 110 37.3 93.1 197 69.9 234 197 211 38.8 127
Active components: 1-Berberine, 2-Capsaicin, 3-Catechin, 4-Cinnamic acid, 5-Curcumin, 6-EGCG, 7-Gingerdiols,
8-Hesperidine, 9-Mangiferin, 10-MTX, 11-Piperine, 12-Quercetin
+: Positive,-: Negative, NS: Nonsubstrate, S: Substrate, NI: Noninhibitor,I: Inhibitor, BBB: Blood-brain barrier,
ADMET: Absorption, Distribution, Metabolism, and Excretion and Toxicity.

The drug compounds designed must possess balance physicochemical properties between their hydrophilicity
and lipophilicity so that they can penetrate the cell membrane and bind with the target receptor. The cell membrane
tends to be lipophilic due to the contents of phospholipid while the cytosol tends to be hydrophilic that contains
protein and water. Log P and Topological Polar Surface Area (TPSA) are the parameters that used to assess the
lipophilicity of compounds. Most of the compounds used in this study met the requirements as lipophilic
compounds, which possess log P < 5and TPSA <140 Å. The three potential compounds (EGCG, hesperidin, and
mangiferin) possess low log P value and TPSA value >140 Å so that they possess wide polar surface area which
means they will hardly to penetrate the cell membrane that is lipophilic and resulted low bioavailability [20]. The

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two parameters reflected the permeability of compounds and were indicated with low permeability value of EGCG,
hesperidin, and mangiferin.
TABLE 5. Metabolism profile of the potential compounds
Parameter 1 2 3 4 5 6 7 8 9 10 11 12
CYP450 2C9 Substrate NS NS NS NS NS NS NS NS NS NS NS NS
CYP450 2D6 Substrate NS NS NS NS NS NS NS NS NS NS NS NS
CYP450 3A4 Substrate S S NS NS NS NS S S NS S S NS
CYP450 1A2 Inhibitor I I NI NI I NI I NI NI NI I I
CYP450 2C9 Inhibitor NI I NI NI I NI NI NI NI NI NI NI
CYP450 2D6 Inhibitor I I NI NI I NI NI NI NI NI I NI
CYP450 2C19 Inhibitor NI NI NI NI I NI NI NI NI NI NI NI
CYP450 3A4 Inhibitor NI I NI NI NI NI NI NI NI NI I I
Active components: 1-Berberine, 2-Capsaicin, 3-Catechin, 4-Cinnamic acid, 5-Curcumin, 6-EGCG, 7-Gingerdiols,
8-Hesperidine, 9-Mangiferin, 10-MTX, 11-Piperine, 12-Quercetin
NS: Non-substrate; NI: Non-Inhibitor; I: Inhibitors; S: Substrate, CYP450: Cytochrome P450
TABLE 6. Toxicity profile of the potential compounds
Parameter 1 2 3 4 5 6 7 8 9 10 11 12
Human Ether-a-go-
go-Related Gene NI WI WI NI WI WI WI WI WI WI WI WI
Inhibition
AMES Toxicity NT T NT NT NT NT NT NT T NT NT NT
Carcinogens NC NC NC NC NC NC NC NC NC NC NC NC
Fish Toxicity LT HT HT HT HT HT HT HT HT LT HT HT
Tetrahymena
HT HT HT HT HT HT HT HT HT HT HT HT
Pyriformis Toxicity
Honey Bee
LT LT HT HT HT HT HT HT HT LT LT HT
Toxicity
Biodegradation NRB NRB NRB RB NRB NRB NRB NRB NRB NRB RB NRB
Acute Oral
III III IV III III IV III III IV II III II
Toxicity
Active components: 1-Berberine, 2-Capsaicin, 3-Catechin, 4-Cinnamic acid, 5-Curcumin, 6-EGCG, 7-Gingerdiols,
8-Hesperidine, 9-Mangiferin, 10-MTX, 11-Piperine, 12-Quercetin
WI: Weak inhibitor, NI: Non-inhibitor, NT: Non-toxic, T: Toxic NC: Noncarcinogen, C: Carcinogen, HT: High
toxic, LT: Low toxic, RB: Readily biodegradable, NRB: Not readily biodegradable

Drug Delivery Model

Based on the result of absorption profile prediction, both mangiferin, EGCG, and hesperidin were considered as
hydrophilic compounds. One of the obstacles that experienced by hydrophilic compounds is that their low
permeability through the physiological barriers that mainly represented by the presence of tight junctions, which
lead to low absorption in the gastrointestinal (GI) tract [21]. The intravenous drug delivery route has been widely
used to administer the hydrophilic drug compounds due to its ability to deliver the drug straight to the systemic
circulation and avoid the absorption mechanism in the GI tract. Nevertheless, this drug delivery route possesses
some limitations, one of them is discomfort and pain experienced by patients during the injection of drugs.
This study suggests drug encapsulation as the model of drug delivery system (DDS) that can be used to deliver
mangiferin, EGCG, and hesperidin to the target of action in the treatment of RA. Drug encapsulation is an efficient
method to improve the pharmacokinetic of a hydrophilic drug. The drug is encapsulated into a carrier that would
protect the drug from degradation. It also has been reported that a hydrophilic drug encapsulated in polymer-based
nanoparticles indicated a better pharmacokinetic profile and bioavailability compared with drug delivery without a
carrier [22].

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FIGURE 4. Ligand-coated liposomes are acquainted by the receptor of cell membrane, so that it would be internalised and then
it could release its content [22].

One of the nanocarriers that could be used in the delivery of mangiferin, EGCG, and hesperidin is liposome,
which are vesicles composed of phospholipid bilayers surrounding an aqueous compartment. To achieve active
targeting, the liposome surface could be coated with ligands and/or antibodies that would make it be internalized by
cell type-specificity so that it could release its content [23].

CONCLUSION
Hesperidin, EGCG, and mangiferin possess the lowest docking energy against TACE enzyme, which indicates
the most comfortable position of ligand in a receptor, compared to both their docking energy against the other
enzymes and the other potential compounds. The ADME-Toxicity prediction shows that hesperidin, EGCG, and
mangiferin possess the optimal pharmacological effect compared to the other compounds. The results indicate that
hesperidin, EGCG, and mangiferin are potential to be developed as RA therapy. However, they all possess low
permeability and would be degradaed in the stage of membrane absorption due to their hydrophilic properties that
lead to a decrease in their bioavailability. An encapsulation using liposome as the drug carrier can be used to
increase the permeability and bioavailability of hesperidin, EGCG, and mangiferin.

ACKNOWLEDGMENT
The authors would like to express their sincere grateful to Department of Pharmacy, Universitas Islam Indonesia
and the administrator of (ChemAxon), iGemDock v2.4 (BioXGEM), Chimera (UCSF) which has facilitated
software or license tools in our computing-based research.

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