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Journal of Chemical and Pharmaceutical Research, 2015, 7(11):385-388

Research Article

ISSN : 0975-7384
CODEN(USA) : JCPRC5

In silico pharmacokinetics analysis and ADMET of phytochemicals of Datura

metel Linn. and Cynodon dactylon Linn.
Soumen Roy$1, Lalit R. Samant*$1,2 and Abhay Chowdhary1,2
1

Department of Virology and Immunology, Haffkine Institute for Training Research and testing, Parel, India
2
Systems Biomedicine Division, Haffkine Institute for Training Research and Testing, Parel, India
$
Authors contributed equally to this work
_____________________________________________________________________________________________
ABSTRACT
Rabies causes acute encephalitis and it still remains an important public health problem in the world. Although
rabies associated fatalities may be prevented with timely immunoprophylaxis, but till date a therapeutic molecule
has remained elusive. Plant secondary metabolites have tremendous potential to be antiviral agents. Cynodon
doctylon and Datura metel are been used in ayurveda for treatment of various aliments. Thus these two medicinal
plants may therefore be explored for potential antiviral activity against Rabies virus by the in-silico model
approach. ADME properties have shown promising results for all the selected phytochemicals. Whereas in silico
toxicity study has shown mor care should be taken while adjusting dose for atropine and scopolamine which are
also good candidate for GPCR receptors. Atropine, scopolamine and phytol has shown potential to become various
inhibitors after subtle modifications.
Keywords: In silico, ADMET, Phytochemicals, Datura, Durva
_____________________________________________________________________________________________
INTRODUCTION
Rabies is an acute viral infection of the central nervous system (CNS) that is usually fatal in humans and animals.
Rabies causes about 55,000 human deaths annually worldwide with 95% of human deaths due to rabies occur
in Asia and Africa. India has the highest rate of human rabies in the world, primarily because of stray dogs, whose
number has greatly increased since a 2001 law forbade the killing of dogs. 20,000 people are estimated to die every
year from rabies in India more than a third of the global toll.[1,2]
Antiviral chemotherapy is an important component in the management of viral diseases. However at present potent
antivirals for clinical usage are available only against limited number of family of viruses (Orthomyxoviridiae,
Herpesviridiae, Retroviridiae). There are no potent antiviral drugs against rabies virus. Therapeutic human rabies
immunoglobulin (HRIG) and vaccine is available against rabies virus but it is ineffective once the virus enters the
central nervous system.There was only one reported case of a female survival from rabies virus by inducing coma
and treating her with combination of known antiviral drugs (Milwakee protocol).[3] Therefore, the search for more
effective antiviral agents against viral infections of the central nervous system (CNS) is a necessary and highly
desirable task. This necessitates the need for development of novel antivirals against rabies virus. Plant secondary
metabolites have tremendous potential to be antiviral agents.
Cynodon dactylon traditionally known as Durva is a medicinal plant used as a folk remedy for anasarca, alaculus,
cancer, convulsions, epilepsy, hypertension, bronchitis, cough and diarrhea. According to ayurvedic system of
medicine it acts as an appetizer, antihelminthic, antipyretic, alexiteric agent and has a wound healing activity. In
homeopathic system of medicine it is used to treat all types of bleeding and skin diseases. It also has a CNS
depressant activity[4,5]

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J. Chem. Pharm. Res., 2015, 7(11):385-388
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Another less studied Indian medicinal plant is Datura, botanical name: Datura metel, although known for its
toxicity, also contains medicinal properties. Datura intoxication typically produces delirium, hyperthermia,
tachycardia, bizarre behavior. But Datura also has medicinal properties. In Indian ayuvedic medicine, datura is used
as a medication for the treatment of hydrophobia which is rabies infection.[6]
Datura has long been used as an extremely effective treatment for asthma symptoms. The active anti-asthmatic
agent is atropine, which causes paralysis of the pulmonary branches of the lungs, eliminating the spasms that cause
the asthma attacks. The leaves are generally smoked either in a cigarette or a pipe. This practice of smoking datura
to relieve asthma has its origins in traditional ayurvedic medicine in India. Datura also has a wide range of
traditional application including epilepsy, hysteria, insanity, heart and skin diseases. It also cures mental diseases
and relieves pain. [7,8]
EXPERIMENTAL SECTION
In silico pharmacokinetics analysis:
Hardware and Software used:
All the computational studies were executed by the PC windows 7 ultimate with Intel Core i3 microprocessor, 8 GB
memory and 64 Bit operating system. We used biological databases such as PubChem. The five phytochemicals
were downloaded in 2D SDF format and further converted to mol2 and SMILES using open babel software.
a) Drug like ness properties and Bioactivity predictions :
Molecular descriptors and drug likeliness properties of compounds were analyzed using the tool Molinspiration
server (http://www.molinspiration.com), based on Lipinski Rules of five [9]. The rule states that most druglike
molecules must have log P 5, molecular weight 500, number of hydrogen bond acceptors 10, and number of
hydrogen bond donors 5. Molecules violating more than one of these rules may have problems with oral
bioavailability. Molinspiration supports for calculation of important molecular properties such as (LogP, polar
surface area, number of hydrogen bond donors and acceptors), as well as prediction of bioactivity score for the most
important drug targets (GPCR ligands, kinase inhibitors, ion channel modulators, enzymes and nuclear receptors
[10]. MOLPSA was used to calculate the percentage of absorption (%ABS) using the equation reported by [11].
Percentage of absorbance = 109 0.345 TPSA.
b) Toxicity risk assessment:
To identify the any undesirable toxic properties of our compounds, Toxicity prediction server
(http://tox.charite.de/tox/) was used. The prediction was based on the functional group similarity for the query
molecules with the in vitro and in vivo validated compounds present in this database. The toxic properties such as
toxicity class, toxic fragment generation, LD50 values in mg/kg , Toxicity targets, drug- relevant properties [c Log
P, Log S (Solubility)], molecular weight, and overall drug-score were calculated[12,13].
RESULTS AND DISCUSSION
Table 1: ADME properties of phytochemicals
Sr
No
1
2
3
4
5

Name
Atropine
Scopolamine
Octadecadienoyl
chloride
Phytol
Ethyl
A-dglucopyranoside;

M
Log
P(>5)
1.77
1.05

ML
volume
(A3)
279.01
277.20

No. of
Rotatable
Bonds
5
5

17.07

318.17

14

20.23

349.38

13

186.14

M. Wt.
(<500Da)

Molecular Formula

HBA
(>10)

HBD
(>5)

MLPSA
(A2)

289.37
303.35

CN1C2CCC1CC(C2)OC(=O)C(CO)C3=CC=CC=C3
CN1C2CC(CC1C3C2O3)OC(=O)C(CO)C4=CC=CC=C4

4
5

0
0

298.89

CCCCCC=CCC=CCCCCCCCC(=O)Cl

8.09

296.53

CC(C)CCCC(C)CCCC(C)CCCC(=CCO)C

6.76

208.21

CCOC1C(C(C(C(O1)CO)O)O)O

-1.65

99.38

49.77
62.3

The molecular descriptors of six natural ligands given in Table 1 were tested to Lipinskis rule of five, interestingly
all the ligands which we selected have molecular weight in the range of 208 304 Da (< 500). Low molecular
weight drug molecules (<500) are easily transported, diffuse and absorbed as compared to heavy molecules.
Molecular weight is an important aspect in therapeutic drug action; If it increases beyond certain limit, the bulkiness
of the compounds also increases correspondingly, which in turn affects the drug action [14]. Number of hydrogen
bond acceptors (O and N atoms) and number of hydrogen bond donors (NH and OH) in the tested compounds were
found to be within Lipinskis limit range from 1-6 and 0 i.e. less than 10 and 5 respectively.
The MLogP (octanol / water partition co efficient) was calculated by the methodology developed by Molinspiration
as a sum of fragment based contributions and correlation factors. Octanol-water partition coefficient logP is used in

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J. Chem. Pharm. Res., 2015, 7(11):385-388
______________________________________________________________________________
QSAR studies and rational drug design as a measure of molecular hydrophobicity. Hydrophobicity affects drug
absorption, bioavailability, hydrophobic drug-receptor interactions, metabolism of molecules, as well as their
toxicity. LogP has become also a key parameter in studies of the environmental fate of chemicals.
Molecular polar surface area (MPSA) or Topological Polar Surface Area (TPSA) is a very useful parameter for
prediction of drug transport properties. Polar surface area is defined as a sum of surfaces of polar atoms (usually
oxygens, nitrogens and attached hydrogens) in a molecule. This parameter has been shown to correlate very well
with the human intestinal absorption, Caco-2 monolayers permeability, and blood-brain barrier penetration. (15)
It was found that the phytochemicals or drugs can be targeted to the CNS with a PSA less than 6070 2.Similar
conclusions were made by van de Waterbeemed based on a study of marketed CNS and non-CNS phytochemicals
(16). Their cutoff for TPSA cutoff for CNS penetration is 90 2 or below. Topological Polar Surface Area (TPSA)
was calculated as described and which was in the range for all the phytochemicals. [10]. O- and N- centered polar
fragments were considered. TPSA has shown to be a very good descriptor characterizing drug absorption, including
intestinal absorption, bioavailability, Caco-2 permeability and BBB penetration. Lipophilicity (log P value) and
Molecular Polar Surface Area (MPSA) or TPSA values are two important properties for the prediction of per oral
bioavailability of drug molecules [17]. Permeability property of compounds were analyzed, the calculated log P
value of six compounds was ranging from -1.65 to 8.09. (<5), which is the acceptable limit for the drugs to be able
to penetrate through bio membranes except for Octadecadienoyl chloride And Phytol.
The highest degree of lipophilicity was found with all the compounds which are an indication for good lipid
solubility that will help the drug to interact with the membranes. TPSA was calculated from the surface areas that
are occupied by oxygen and nitrogen atoms and by hydrogen atoms attached to them. Thus, the MolPSA is closely
related to the hydrogen bonding potential of a compound [18]. In our study, all ligands exhibited 77% to 95%
absorption, indicates good bioavailability by oral route. Good bioavailability is more likely for compounds with 10
rotatable bonds and MolPSA of 140 [19]. Molecular volume (ML volume) determines transport characteristics
of molecules, such as intestinal absorption or blood-brain barrier penetration. Volume is therefore often used in
QSAR studies to model molecular properties and biological activity it was within the range for all the
phytochemicals.
As the number of rotatable bonds increases, the molecule becomes more flexible and more adaptable for efficient
interaction with a particular binding pocket. Interestingly, three compounds have 3-5 rotatable bonds and flexible
whereas phytol has 13 and Octadecadienoyl chloride has 14 rotatable bonds.
Table 2 : Toxicity Prediction of phytochemicals
Sr. No
1
2
3
4
5

Name
Atropine
Scopolamine
Octadecadienoyl chloride
Phytol
Ethyl |A-d-glucopyranoside

LD50 value mg/KG body weight

75
270
5000
5000
23000

Toxicity class
III
III
V
V
VI

Toxic fragment formation

None
None
None
None
None

Remark
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic

Class I: fatal if swallowed (LD50 5 mg/kg)

Class II: fatal if swallowed (5 < LD50 50 mg/kg)
Class III: toxic if swallowed (50 < LD50 300 mg/kg)
Class IV: harmful if swallowed (300 < LD50 2000 mg/kg)
Class V: may be harmful if swallowed (2000 < LD50 5000 mg/kg)
Class VI: non-toxic (LD50 > 5000 mg/kg)

From table 2 it was clear that LD50 value was highest for Ethyl |A-d-glucopyranoside and was lowest for atropine
which indicates while choosing the dose range for atropine more care should be taken. Depending on the Toxicity
classes are defined according to the globally harmonized system of classification of labelling of chemicals (GHS) .
From above result it was clear that atropine and scopolamine should be given with more caution under experimental
study to avoid any loss of animal due to toxicity which may in turn affect the statistical analysis of the experiment.
Table 3: Bioactivity of the phytochemicals
Sr.
No
1.
2.
3.
4.
5.

Phenolic acid
Atropine
Scopolamine
Octadecadienoyl chloride
Phytol
Ethyl |A-d-glucopyranoside

GPCR
Ligand
0.44
0.58
0.11
0.11
-0.25

Ion channel
modulator
0.26
0.23
0.07
0.16
0.09

387

Kinase
inhibitor
-0.09
0.06
-0.12
-0.32
-0.54

Nuclear receptor
ligand
-0.06
0.11
0.06
0.35
-0.78

Protease
inhibitor
0.13
0.27
-0.07
0.00
-0.40

Enzyme
inhibitor
0.21
0.35
0.18
0.31
0.38

Lalit R. Samant et al
J. Chem. Pharm. Res., 2015, 7(11):385-388
______________________________________________________________________________
Drug likeliness property of five compounds against GPCR ligand, ion channel modulator, kinase inhibitor, nuclear
receptor ligand, protease inhibitor and enzyme inhibitory activity were studied and summarized in Table 3. The
molecule having bioactivity score more than 0.00 is likely to possess considerable biological activities, values -0.50
to 0.00 are expected to be moderately active and if score is less than -0.50, it is presumed to be inactive [20]. The
results of the present study demonstrated that the investigated compounds were biologically active and produced the
physiological actions by interacting with GPCR ligands, nuclear receptor ligands, inhibit protease and other
enzymes. GPCR ligand-based signaling cascade was used for the development of a new functional drug with
increased binding selectivity profile and less undesirable effects. Bioactivity score for GPCR ligand was found to be
0.58 &0.44 for scopolamine and atropine which indicates they could bind GPCR effectively. Ion channel
modulators allowed the movement of charged particles across cell membranes and are important therapeutic targets
which are modulated by a range of therapeutic drugs. Bioactivity score for ion channel modulator activity was in
between 0.09 and 0.26 and it was highest for atropine. Kinase inhibitors for development of selective inhibitors that
can block or modulate diseased signaling pathways are considered a promising approach for drug development it
was having range from -0.06 to -0.54 [21]. Bioactivity scores for nuclear receptor ligand, protease inhibitor and
enzyme inhibition was found to be in the range of --0.78to 0.35 and was highest for Phytol, -0.40 to 0.27 was
highest for scopolamine and 0.18 to 0.38 respectively and was promising for phytol and Ethyl |A-d-glucopyranoside
. Overall Scopolamine, atropine and phytol shows some potential be active candidate which can be modified
further to enhance their bioactivity.
Datura plant contains high levels of tropane alkaloids such as atropine, hyoscyamine and scopolamine.[22] Rabies
virus binds to acetylcholine receptors and enter the neurons via anterograde axonal transport route. [23,24] Atropine
is a competitive inverse agonist for the muscarinic acetylcholine receptor and which is abundantly present in Datura.
[25] However, its mechanism of inhibition and interaction with the virus is yet to be elucidated hence the present
study intends to assess the in silico model for antiviral activity against rabies virus by looking at the interaction of
the atropine molecule along with the ADMET properties.
Acknowledgements
Authors are grateful to the Haffkine Institute for Training, Research & Testing for providing the opportunity to
conduct present investigation.
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