Screening of Potent Phytoconstituent of "Tinospora Cordifolia" used in Coronil against Covid 19 Virus Protein Propain like Protease PLpro and ACE ...
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
Screening of Potent Phytoconstituent of “Tinospora Cordifolia”
used in Coronil against Covid 19 Virus Protein Propain like
Protease PLpro and ACE Spike Protein Using Virtual Screening
Shrinit Chaurasiya1, Ashwani Mishra2
Department of Pharmacy, Barkatullah University, Bhopal, Madhya Pradesh, India
*Corresponding Author
Email Id: shreenit9@gmail.com,ashwanipharma@gmail.com
ABSTRACT
In this research work an attempt was made to scan the potent phytoconstituent of an
important plant Tinospora Cordifolia present in the formulation Coronil formulated by Divya
Patanjali. In this work, four phytoconstituents were screened Berberine,
Tetrahydropalmatine, Furanoid and Tinocordifolioside. The virtual screening of the
Phytoconstituents were done on the basis of Physicochemical, Biopharmaceutical properties,
predicted bioactivity and drug likeliness properties. The result revealed that Berberine
exhibited best interaction energy of ACE spike protein of the COVID 19 as compared
toTetrahydropalmatine, Furanoid and Tinocordifolioside. This phytoconstituents berberine
was further insilico analysed on the basis of toxicological properties so that its safety could
be predicted. The result of toxicological properties revealed that Human Hepatotoxicity and
human ether -a-go-go related gene based toxicity were absent in all the phytoconstituents.
The DILI predicted by Berberine and Tetrahydropalmatine but with very less
probability .This exhibited that these phytoconstituents have good safety profile.
Key words: Tinospora Cordifolia, COVID 19, phytoconstituents, Berberine, Coronil
INTRODUCTION scheme. The official data of Patanjali
Coronil a formulation prepared by Ayurved's Swasari revealed that after the
Patanjali Ayurved which is a producer of launching of this formulation Coronilkit.
quality Herbomineral preparations. This There is a recorded sale worth Rs 250
Divya Yog Mandir Trust and Patanjali crore in four months [2].
Yog Peethal so grow different endangered
herbs in its farmland and monitor it. The It has been observed that PLpro is an
Patanjali Ayurveda follows Good important corona virus enzyme and its
Manufacturing Practices (GMP) in required to generate functional replicase
Manufacturing and also followed number complex via process of viral polyprotein, it
of standard quality control parameter for also enables Viral spread [3,4].
developing best formulation [1].
Similarly role of angiotensin converting
Coronil has also received certification enzyme 2 (ACE2) for infection and
from AYUSH Ministry as per WHO pathogenesis by SARS-CoV-2 is an
norms. This formulation can be used as potential research area. An increased
“supporting measure in Covid-19” and an susceptibility to infection in individuals
immuno-booster. Same formulation also with higher levels of circulating indicated
received the Certificate of Pharmaceutical that interaction with ACE2 might result in
Product (CoPP) from the Ayush section of disseminated virus-receptor complexes.
(CDSCO) Central Drugs Standard Control This may increase pathogenesis andvirus
Organisation as per the WHO certification acquisition [5,6].
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
People suffering from COVID-19 have Tinospora Cordifolia (Guduchi) is a large,
had a number of Symptoms Perennial, Deciduous, Glabrous, climbing
reported-ranging from mild symptoms to shrub of weak and Fleshy stem found
severe illness. These Symptoms may start throughout India. It is widely used plant in
appearing 2-14 days after exposure to the Folk and Ayurvedic Systems of Medicine.
Virus.
It showed Astringent, Thermogenic,
Some of the symptoms of COVID-19 are Anodyne, Anthelmintic, Alterant,
Fever or Chills, Cough. Shortness of Antiperiodic, Antispasmodic, Anti-
Breath, Muscle or Body aches and Fatigue, inflammatory, Antipyratic, Antiemetic,
Headache. New loss of Taste or Smell Digestive, Carminative, Appetise,
[7,8]. Stomochic, Constipating, Cardiotonic,
Heamatinic, Expectorant, Galacto-purifier
Plant Profile and tonic, Antimalarial, Antiviral [11].
Tinospora Cordifolia, which is known by
the common names gurjo, Heart-Leaved The above explanation and the use of this
Moonseed, Guduchi, and Giloy, is an plant in the development of Coronil
herbaceous vine of the family formulation an Attempt was made to find
Menispermaceae indigenous to tropical out the different key chemical constituents
regions of the Indian subcontinent. Despite of this plant and then out of these best
centuries of use in traditional medicine to phytoconstituents are subjected for insilico
treat various disorders. screening for the selection. Along with it a
market survey was also done in which
Botanical Name: TinosporaCordifolia, some of the Ayurvedic formulation
Kingdom : Plantae, containing this plant has been tabulated in
Family: Menispermace this work.
Part used: Stem, Leaves, Fruit, Bark etc.
[9,10].
Fig. 1. Leaf and fruits of Tinospora Cordifoli
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
Table -1: Some Phytoconstituents of Tinospora Cordifolia Reported
Type of chemical Active principles Part in which
present
Alkaloids Berberine, Palmatine, Stem
(Tikta-Bitter Principle)
Tembetarine, Magnoflorine, Root
Choline, Tinosporin, Isocolumbin, Palmatine,
Glycosides 18-norclerodane glucoside, Furanoidditerpene Stem
glucoside, Tinocordiside,
Tinocordifolioside,
Cordioside, Cordifolioside A, Cordifolioside B,
Syringin, Syringin-apiosylglycoside,
Palmatosides C, Palmatosides F,
Cordifoliside A, Cordiofoliside B,
Cordifoliside C, Cordifoliside D, Cordifoliside E
Diterpenoid lactones Furanolactone, Clerodane derivatives and Whole plant
[(5R,10R)-4R-8R-dihydroxy-2S-3R:15,16-
diepoxy-cleroda-13 (16), 14-dieno-17,12S:
18,1S-dilactone] and Tinosporon, Tinosporides,
Columbin and, Jateorine,
Steroids β -sitosterol, δ-sitosterol, 20 β- Aerial part
Hydroxyecdysone. Stem
Ecdysterone, Makisterone A,
Sesquiterpenoid Tinocordifolin. Stem
Aliphatic compound Octacosanol, Heptacosanol, Whole plant
Miscellaneous Nonacosan-15-one Whole plant
3,(α,4-di hydroxy-3-methoxy-benzyl)-4-(4- Root
Compounds Whole plant
hydroxy-3-methoxy-benzyl)-tetrahydrofuran.
Insilico PREDICTION STUDY AND Papaine PLpro Protein were observed as
MOLECULAR DOCKING per the amino acid reside they have using
Validation of Protein Ramachandran plot [13].
In this in-silico validation process both the
protein ACE 2 Receptor and Corona Virus
Fig. 2. Ramachandran Plot of Corona Virus Protein papaine PLpro
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
Fig.2. Ramachandran Plot of Crystal structure of SARS-CoV-2 spike receptor ACE 2
POCKET DETERMINATION OF BOTH PROTEINS
Covid 19 ACE 2 Receptor Protein Structure
Fig.3. ACE 2 Receptor Protein pockets
Fig.4. Corona Virus Protein papaine PLpro pockets
ACE 2 Receptor Protein revealed 5 Corona Virus Protein papaine PLpro
pockets, Pocket-1 shown orange exhibited 5 pocket 1 which is the biggest
color .Yellow color exhibited by the pocket Pocket 2 shown by orange color,
Pocket 2 .Magenta color showed by pocket Pocket 3 shown by pink color, pocket 4
3, Blue color exhibited by the pocket 4 and was exhibited by the yellow color pocket 5
Green color showed by the pocket 5 of the was exhibited by cyan colour.
protein.
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
Prediction of Physiochemical and phytoconstituents were subjected to
Biopharmaceutical Properties in-silico screening based prediction
Prediction of Physiochemical properties model.The toxicity based prediction
and biopharmaceuticalwere performed by models are based on Lipinski Rule, Pfizer
usingstrings and SDF/TXT formatted files Rule,GSK Rule and golden triangle rule.
they were supported molecular submission These two modules were suitable for the
approaches. The module was suitable for prediction of molecules.
the evaluation of visually screened
molecules .This also helped in the scrutiny Molecule Docking study of selected
of best molecule which had all the Molecule -
acceptablephysciochemicaland In molecular docking study All four
biopharmaceutical [14, 15]. phytoconstituents of the Tinospora
Cordifolia was phytoconstituents
Drug likeliness Properties and Berberine, Tetrahydropalmatine, Furanoid
Prediction of Toxicity and Tinocordifolioside were docked with
Prediction of drug likeliness properties and ACE 2 Receptor and papaine PLpro
toxicitywere performed by protein [16, 17].
usingstrings .Different string of
Table -1 Different Physiochemical Properties of Phytoconstituents of
Tinospora Cordifolia
Parameters Berberine Tetrahydropalmatine Furanoid Tinocordifolioside
miLogP 0.20 2.75 1.94 0.46
TPSA 40.82 40.17 29.46 128.9
natoms 25 26 12 29
MW 336.37 355.43 170.25 412.48
nON 5 5 2 8
nOHNH 0 0 1 4
nviolations 0 0 0 0
nrotb 2 4 2 4
Volume 296.30 332.77 375.80
Predicted Bioactivity
GPCR ligand 0.11 0.18 0.67 0.29
Ion channel 0.71 0.02 0.31 0.20
modulator
Kinase inhibitor 0.27 0.37 0.95 -0.20
Nuclear receptor 0.78 0.36 0.34 0.39
ligand
Protease inhibitor 0.35 0.21 0.93 0.30
Enzyme 0.04 0.12 0.74
inhibitor
Table -2 Different properties Drug Likeliness properties and Toxicity prediction
Parameters Berberine Tetrahydropalmatine Furanoid Tinocordifolioside
Drug Likeliness Properties
Lipinski Rule Accepted Accepted Accepted Accepted
Pfizer Rule Rejected Accepted Accepted Accepted
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Volume 1 Issue 2
GSK Rule Rejected Accepted Accepted Rejected
Golden Accepted Accepted Rejected Accepted
Triangle
Toxicity Prediction
hERG -- -- --- ---
Blockers
H-HT --- -- -- --
DILI + + --- ---
PPB 93.1% 83% 45.312% 50.4%
VD 1.2 1.1 1.3 0.8
BBB +++ +++ ++ --
Penetration
Table-3 Result of interaction of Berberine with the Covid 19 virus protein
PapainePLpro ACE2 Inhibitors
Pocket 1 -6.29 Pocket 1 -7.57
Pocket 2 -6.96 Pocket 2 -6.66
Pocket 3 -6.00 Pocket 3 -6.00
Pocket 4 -5.97 Pocket 4 -6.92
Pocket 5 -6.98 Pocket 5 -5.50
Fig. 5. Corona Virus Protein ACE 2 Receptor with Berberine ligand in to the first pocket
shows capturing the ligand in to the pocket
Fig.6. Corona Virus Protein papaine like protease receptor with the berberine ligand in to
the first pocket shows capturing of the ligand in to the pocket.
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Volume 1 Issue 2
RESULT AND DISCUSSION Which is only required for highest
The aim of choosing this research work is permeability.
to identify the potential of the Tinospora
Cordifolia, which is known by the The molecular weight of the Berberine
common names Gurjo, Heart-Leaved was also in the acceptable range as per
Moonseed, Guduchi, and Giloy, Giloy. drug likeliness property of
Through literature survey four potent Phytoconstituents as compared to
phytoconstituents of the Giloy were Tetrahydropalmatine, Furanoid and
selected those are Berberine, Tinocordifolioside.
Tetrahydropalmatine, Furanoid and
Tinocordifolioside. Number of rotatable bond was more in
Tetrahydropalmatine and Tinocordi
1. The protein of Corona Virus Protein folioside that is four but they were two
papainePLpro had resolution of 2.59 Å with Furanoid and Berberine. The
and it’s a crystal structure confirmed calculated Log P showed the highest
by Xray diffraction method. In the lipopilicity of the berberine as
Ramchandran plot. Out of 1229 compared to rest of the 3 other
residue 966 were in most favoured phytoconstituents.
region, 126 residues were in
Additional allowed region and 2 3. Both the protein exhibited 5 pockets
residues were present in generously the specification of pocket mention in
allowed region. the table number 4. After the in-silico
binding of the ligand Berberine with
It could be extracted that more than the two proteins propain like protease
88.8% residue of the protein are in the PLpro and ACE spike protein of
acceptable regions. In this protein plot COVID 19 virus.
statistics of protein structure of
SARS-CoV-2 spike receptor ACE 2 4. Drug likeliness properties could be the
which had 791 residues 650 residues best prediction parameter which was
were in favored regions, 54 residues exhibited by acceptability of the
were in additional allowed regions and molecule as per the Lipinski Rule,
no residue was in disallowed regions. Pfizer Rule, GSK Rule and golden
The resolution of the protein was 2.45 triangle rule. In this study Lipinski
Å. Rule and golden triangle rule both
were accepted by all the
2. The first step of identification and phytoconstituents of Tinospora
analysis of these phytoconstituents to Cordifolia.
determine its drug related property and
physiochemical property which could The result of toxicological properties
be used to scrutinize best phyto revealed that Human Hepatotoxicity
constituents. All the phytoconstituents and human ether -a-go-go related gene
showed no violation and the molecular based toxicity were absent in all the
weight of all the phytoconstituents was phytoconstituents. The DILI predicted
under the limit of Lipinski rule of 5. by Berberine and Tetrahydropalmatine
but with very less probability .This
Topological polar surface area of exhibited that these phytoconstituents
berberine was better than all other have good safety profile .
constituents even Tinocordifolioside
exhibited highest TPSA 128.9A2
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
5. The Result of the target based docking could be utilize in the future research
exhibited that molecular ID 1 that was work for developing formulation and
Berberine acted very well with ACE2 clinical trial study of the formulation .
inhibitors of SARS Co V since its had
energy -7.5 K/cal with the first pocket CONCLUSION
which was the biggest pocket in the It could be concluded from this in-silico
protein and it showed high energy of research work that there are many
binding with -6.98 K/cal with PL pro phytoconstituents of Indian medicinal
monomer with the 5th pocket with was plant possess antiviral activity against
the smallest pocket in the protein COVID 19 Virus. In this in silico
cavity. The overall result of this investigation Berberine were selected as
in-silico study revealed that best phytoconstituents, though its
phytoconstituent of Giloyberberine has applicability and confirmation for the
a potential to interact with the ACE efficient treatment of COVID 19 would
spike protein of the COVID 19 and this need further clinical research.
Fig.7. Different poses of Protein of COVID 19 Virus ACE2 inhibitors in the first pocket.
Table-4: Computer generated Images of Phytoconstituents on the Basis of Different
Properties
Phytoconstituents Structure Upper limit Lower limit Compound
properties
Berberine
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International Journal of Pharmaceutical Science & Innovation
Volume 1 Issue 2
Tetrahydropalmatine
Furanoid
Tinocordifolioside
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