ArticlePDF Available

In silico inquest reveals the efficacy of Cannabis in the treatment of post-Covid-19 related neurodegeneration

Authors:

Abstract and Figures

Coronavirus (SARS-CoV-2), the causative agent of the Covid-19 pandemic has proved itself as the deadliest pathogen. A major portion of the population has become susceptible to this strain. Scientists are pushing their limits to formulate a vaccine against Covid-19 with the least side effects. Although the recent discoveries of vaccines have shown some relief from the covid infection rate, however, physical fatigue, mental abnormalities, inflammation and other multiple organ damages are arising as post-Covid symptoms. The long-term effects of these symptoms are massive. Patients with such symptoms are known as long-haulers and treatment strategy against this condition is still unknown. In this study, we tried to explore a strategy to deal with the post-Covid symptoms. We targeted three human proteins namely ACE2, Interleukin-6, Transmembrane serine protease and NRP1 which are already reported to be damaged via Covid-19 proteins and upregulated in the post-Covid stage. Our target plant in this study is Cannabis (popularly known as ‘Ganja’ in India). The molecular docking and simulation studies revealed that Cannabidiol (CBD) and Cannabivarin (CVN) obtained from Cannabis can bind to post-Covid symptoms related central nervous system (CNS) proteins and downregulate them which can be beneficial in post-covid symptoms treatment strategy. Thus we propose Cannabis as an important therapeutic plant against post-Covid symptoms. Communicated by Ramaswamy H. Sarma
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=tbsd20
Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
In silico inquest reveals the efficacy of Cannabis
in the treatment of post-Covid-19 related
neurodegeneration
Indrani Sarkar, Gargi Sen, Malay Bhattyachariya, Subires Bhattacharyya &
Arnab Sen
To cite this article: Indrani Sarkar, Gargi Sen, Malay Bhattyachariya, Subires Bhattacharyya
& Arnab Sen (2021): In silico inquest reveals the efficacy of Cannabis in the treatment of post-
Covid-19 related neurodegeneration, Journal of Biomolecular Structure and Dynamics, DOI:
10.1080/07391102.2021.1905556
To link to this article: https://doi.org/10.1080/07391102.2021.1905556
View supplementary material
Published online: 02 Apr 2021.
Submit your article to this journal
View related articles
View Crossmark data
In silico inquest reveals the efficacy of Cannabis in the treatment
of post-Covid-19 related neurodegeneration
Indrani Sarkar
a
, Gargi Sen
a,b
, Malay Bhattyachariya
b
, Subires Bhattacharyya
c
and Arnab Sen
a,c
a
Bioinformatics Facility, Department of Botany, University of North Bengal, Siliguri, India;
b
Department of Tea Science, University of North
Bengal, Siliguri, India;
c
Biswa Bangla Genome Centre, University of North Bengal, Siliguri, India
Communicated by Ramaswamy H. Sarma
ABSTRACT
Coronavirus (SARS-CoV-2), the causative agent of the Covid-19 pandemic has proved itself as the
deadliest pathogen. A major portion of the population has become susceptible to this strain. Scientists
are pushing their limits to formulate a vaccine against Covid-19 with the least side effects. Although
the recent discoveries of vaccines have shown some relief from the covid infection rate, however,
physical fatigue, mental abnormalities, inflammation and other multiple organ damages are arising as
post-Covid symptoms. The long-term effects of these symptoms are massive. Patients with such symp-
toms are known as long-haulers and treatment strategy against this condition is still unknown. In this
study, we tried to explore a strategy to deal with the post-Covid symptoms. We targeted three human
proteins namely ACE2, Interleukin-6, Transmembrane serine protease and NRP1 which are already
reported to be damaged via Covid-19 proteins and upregulated in the post-Covid stage. Our target
plant in this study is Cannabis (popularly known as Ganjain India). The molecular docking and simu-
lation studies revealed that Cannabidiol (CBD) and Cannabivarin (CVN) obtained from Cannabis can
bind to post-Covid symptoms related central nervous system (CNS) proteins and downregulate them
which can be beneficial in post-covid symptoms treatment strategy. Thus we propose Cannabis as an
important therapeutic plant against post-Covid symptoms.
ARTICLE HISTORY
Received 25 December 2020
Accepted 15 March 2021
KEYWORDS
Covid19; post-Covid
symptoms; Cannabis; post-
Covid neural degeneration;
docking and
molecular simulation
Introduction
Coronavirus disease (Covid-19) emerged from Wuhan, China
in the last quarter of 2019 was declared as a pandemic in
March 2020 by World Health Organization (Lin et al., 2020,
Singh et al., 2020). Several attempts of defeating this tiny
virus have been taken so far. However, to date, there is no
major success to count. Globally the number of affected peo-
ple is increasing day by day along with the number of death
caused by Covid. Around 10 million people have already
been affected in India and the number is huge (around 77
million) worldwide (https://Covid19.who.int/). The human civ-
ilization is currently experiencing tremendous pressure to
fight against this minute but noxious virus. Nearly 1.69 mil-
lion people have died due to Coronathe number is count-
ing. Though, 43.3 million people have recovered (https://
Covid19.who.int). However after recovery, patients are experi-
encing different post-Covid symptoms. Virtually all major
organs are affected by the covid-19 virus causing headache,
dizziness, increased risk of heart attack, lung fibrosis, kidney
failure, rheumatoid arthritis and neuro-degeneration-related
problems (Cao, 2020; Davido et al., 2020). Among them,
neurological complications have emerged as major symp-
toms in post-Covid impediments. This is not at all surprising,
since neurological disorders have long been reported as a
parallel symptom of Coronavirus infection along with respira-
tory distress (Davido et al., 2020). However, this time neuro-
logical abnormalities initiated by Covid-19 are too
widespread on the overall population (Wijeratne & Crewther,
2020). Some post-Covid patients are experiencing delirium:
they are confused, disorientated and agitated. Subsequently,
deterioration of myelin sheath (a fatty coating that protects
neurons) was reported indicating a sign similar to multiple
sclerosis (Troyer et al., 2020). Moreover, cases with acute
neuropsychiatric symptoms after Covid-19 treatment is
increasing. The intensity and diversity of neurological syn-
dromes as post-Covid disorders is on the rise and the list
now includes stroke, brain hemorrhage even memory loss
(Troyer et al., 2020, Bonaventura et al., 2020). Although two
major neurodegenerative disorders Parkinsonism and
Parkinsons diseases (PD) have yet not been listed as co-
Covid or post-Covid symptoms, however, recent studies
reported anti-Covid antibodies in cerebrospinal fluid (CSF) of
individuals with Cognitive disorders (Raphael et al., 2020).
Since the neural and immune cells serve as reservoirs of
latent Covid, it may be possible that it can contribute to
delayed neurodegenerative processes as post-Covid symp-
toms. The neuroinvasive potential of Covid-19 is extremely
dynamic. The virus spread from the respiratory tract to the
CONTACT Arnab Sen senarnab_nbu@hotmail.com Department of Botany, School of Life Sciences, BIF, University of North Bengal, Raja Rammohunpur,
Darjeeling, Siliguri, 7340013, India.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2021.1905556.
ß2021 Informa UK Limited, trading as Taylor & Francis Group
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2021.1905556
CNS via a retrograde axonal transport from the peripheral
nerves such as the olfactory nerve, or via hematogenous
spread (Marshall, 2020; Raphael et al., 2020). After the
entrance, this virus may induce neuron cell death leading to
extreme neurological damage. Notably, the key protein
Angiotensin-Converting Enzyme 2 (ACE2) that Covid-19
hijacks for host intracellular invasion remains present on neu-
ron and glial cells. Neuronal death and up-regulation of TNF-
alpha, IL-1-beta, IL-6 have been reported to be associated
with Covid and post Covid symptoms (Behl et al., 2020).
Recent studies reported high levels of ACE2 expression in
oral epithelial indicating the oral cavity as one of the major
gateways of Covid to the human body. Along with them, the
NLR family pyrin domain containing 3 (NLRP3) has emerged
as major targets of Covid-19 (Yin et al., 2017). The significant
roles of these proteins in the maintenance of neural homeo-
stasis are well understood. Thus, any compound with the
ability to restore the normal conformation of these afore-
mentioned proteins and most importantly with the ability to
neurogenesis can be regarded as a cure to post Covid
neuro-disturbance (Yin et al., 2017).
From ancient times, the practice of phytomedicine is
popular in India and several phytochemicals have been
reported as probable therapeutic targets against Covid-19
(Singh et al., 2020a). We previously reported the use of
Clerodendrum,Ocimum tenuiflorum and Justicia adhatoda
derived compounds as anti-covid agents (Kar et al., 2020a,
b). In another work we testified the use of
Dextromethorphan along with Prednisolone and
Dexamethasone can be effective against Covid-19 (Sarkar &
Sen, 2020). However, so far the Post-Covid complications
are concerned, very little work has been done. A recent
study reported Cannabis as a source of anti-Covid com-
pounds (Russo et al., 2007). Cannabis has an immune-regu-
latory, anti-inflammatory effect (Russo et al., 2007). Along
with this it also has an influence on cardiovascular disease
and hypertension (Clerkin et al., 2020). Most interestingly,
cannabinoids (extracted from Cannabis) have a role in adult
neurogenesis and are effective in the proliferation of neural
stem cells and neural progenitor cells (Russo et al., 2007).
This is of utmost concern since one of the main problems
in post-Covid patients is neurodegeneration. Moreover, sev-
eral countries of North and South America, Australia, Africa
and Northwestern Asia have legalized Cannabis for its medi-
cinal marvel (https://en.wikipedia.org/wiki/Legality_of_canna-
bis). It seems the medicinal possessions of this plant with
some religious aspect in India have overcome its addictive
adverse effects.
In the present study, we have used the in-silico docking
approach along with molecular dynamics and simulation
techniques to venture whether Cannabis can act as a medi-
cinal wonder against post- Covid neuro-complications.
Materials and methods
Selection of ligands based on physio-chemical nature
The GCMS data of Cannabis sativa and C. indica have been
reported previously (Isahq et al., 2015; Tayyb & Shahwar,
2015). All the major compounds from those reports were ini-
tially considered for this study. Lipinskis rule, which is con-
sidered to be the rule of thumbfor determining the
druggability score of any compound, was exploited in this
study (Zhang & Wilkinson, 2007). All considered phytochemi-
cals were examined with the four major factors including
molecular weight, number of hydrogen bond donors and
acceptor along with octanol-water partition coefficient (log
P) value. Adsorption, distribution, metabolism and excretion
(ADME) properties of select ligands were determined via
SWISS ADME server. Considered ligands with good druggabil-
ity scores were finally used for this analysis (Daina et al.,
2017). The structures of those ligands were downloaded
from NCBI PubChem database. Those ligands were prepared
for docking after choosing the correct torsion angles through
AutoDock Vina software (Trott & Olson, 2010).
Selection of target proteins
Total four proteins namely Angiotensin-converting enzyme
2 (ACE2) (PDB id 6CS2), Transmembrane protease serine 2
(TMPRSS2) (PDB id 3NPS), NRP1 protein (PDB id 7BP6) and
Interleukin-6 (IL6) (PDB id 1ALU) were considered for this
study. All of them are crucial for both the entrance of
Covid-19 into the host cell as well as post-Covid neurode-
generative symptoms. Moreover, their high-quality NMR
structures are already available in the PDB database
(https://www.rcsb.org/) as mentioned above. We selected
6CS2 for ACE2 protein since it was a docked structure
showing the interaction between Covid spike protein and
ACE2 from the human. We removed the spike protein from
the structure and extracted the structure of ACE2 from
6CS2 for further analysis. We have detatched all the inter-
acting ligands from the downloaded structures. Finally,
those proteins were prepared for docking study after
removing the water molecules and adding polar Hydrogen
molecules. Gasteiger charges were assigned to each protein.
The PDB versions of protein structures were converted into
PDBQT forms and the target proteins were ready for the
final molecular docking study.
Molecular docking
The site-specific grid-based docking (also known as redock-
ing) is an approach where ligands are docked to an induced-
fit structure of the receptor. Previous studies have already
pointed out residues of ACE2 and TMPRSS2 proteins those
are interacting with Covid proteins. It has been reported that
Tyr 41, Gln 42, Lys 353 and Arg 357 from N terminal region,
Asp 30 and His 34 from middle region and Gln 24 and Met
82 from C terminal region of ACE2 interact with the Covid
protein (Prajapat et al., 2020). Similarly His296, Glu299,
Pro301, Leu302, Lys340, Lys342, Gly439, and Ser441 from
TMPRSS2 protein has been reported to build a network with
Covid proteins. Hence for ACE2 and TMPRSS2 protein we
took a site specific docking approach. We used three differ-
ent grids for N terminal, middle region and C- terminal parts
of ACE2 protein. However for TMPRSS2 we specified one grid
2 I. SARKAR ET AL.
to target the aforementioned amino acid residues. However,
the interacting amino acids of Il-6 and NRP1 are still not well
characterized. Hence, we have to use blind docking tech-
nique for those two proteins. Hence, it was a need for us to
first search all possible binding cavities where CBD and CVN
can bind and then target the best cavity through site-specific
docking with optimized grid volume. The re-docking was
done through AutoDock Vina software.
Energy minimization and molecular dynamics study
Dock scores were compared and the four best-docked com-
pounds were selected for energy minimization and molecular
dynamics study. This dynamics study was carried out via
GROMACS (Pronk et al., 2013). Four best-docked complexes
were considered for simulation with Gromacs96 53a6 force
field. Topologies for this analysis were generated in GROMACS
software. The number of particles in the system (N), systems
volume (V) and total energy in the system (E) known as NVE
ensemble were considered as macroscopic variables.
Thermostat and Barostat were introduced for MD simulation at
the NVE system. Constant temperature (303 K) and constant
pressure (1 bar) were employed. MD simulation was performed
for a 100 ns time scale and 10,000 steps of energy minimiza-
tion through the steepest descent mechanism. Root-mean-
square deviation (RMSD), as well as the root, mean square fluc-
tuation (RMSF) of the complexes, was estimated to get an idea
about the MD trajectories. All the in silico analyses including
docking and simulation studies have been done twice.
MM-GBSA calculation
Molecular mechanics generalized Born surface area (MM/
GBSA) is one of the most popular approaches in estimating
the free energy (DG) of a ligand binding reaction since it is
more accurate than most of the molecular docking techni-
ques and also computationally easier. MM/GBSA depends
upon the parameter used for simulation studies and also on
the binding cavities. Overall, as per the thermodynamic rule,
a negative value of DG indicates a thermodynamically
favourable reaction whereas a positive DG value points
thermodynamically non-favourable reaction. In this study,
our main aim was to reveal whether, CBD and CVN upon
binding to the four target protein give a fisable DG value or
not. Molecular mechanics-generalized Borne surface area
(MM-GBSA) was estimated via g_mmpbsa embedded in
Gromacs software. It estimated the free energies of binding
(DG
bind
) of the selected protein-ligand complexes. This is an
approach using the optimized potential for liquid simulations
(OPLS) force field in combination with molecular mechanics
energies (EMM), solvation model for polar solvation (GSGB)
surface generalized Born (SGB) and a non-polar solvation
term (GNP) (Al-Khafaji et al., 2020; Mittal et al., 2020; Sarma
et al., 2020). The total free energy of binding of each pro-
tein-ligand complex was calculated as:
DGbind ¼DGcomplexDGprotein þDGligand

Result and discussion
Effect of cannabis-derived compounds on post-Covid
CNS problem
A molecular docking study was adapted for exploring the
effectiveness of Cannabis derived Phyto-compounds in the
post-Covid era. A total of eight potential compounds were
selected for this study (Supplementary File 1). Among them,
two compounds namely Cannabivarin (CVN) and Cannabidiol
(CBD) showed the most promising results. Their physico-
chemical properties supported their candidature as drug
molecules (Supplementary File 2). CBD showed the best
docking with ACE2 (PDB id 6CS2) (Figure 1a) and interleukin
(IL)-6 (PDB id 1ALU) (Figure 2a). Their docking scores were
8.9 kcal/mol and 8.2 kcal/mol respectively. The interacting
amino acids for ACE2 involved Asp-30 and His-34 which are
previously reported to interact with Covid-19 protein. Asn63,
Leu64, Met67 of IL-6 protein were revealed to be interacting
with CBD.On other hand, CVN docked with TMPRSS2 (PDB id
3NPS) (Figure 3a) and NRP1 protein (PDB id 7BP6) (Figure 4a)
with 8.7 kcal/mol and 8.5 kcal/mol energy respectively.
Leu302, Lys340, Lys342 were the interacting network of
TMPRSS2 (these three amino acids also interact with Covid
protein), whereas Ser80, Lys81 and Gly64 from D chain of
NRP1 (7BP6) network with CVN. After MM-GBSA calculation,
it was evident that all the protein-ligand complex were
showing free energy change of more than 30.0 kJ/mol
(Table 1). A previous report (Prajapat et al., 2020) listed
down the MM/GBSA scores of some FDA approved drug
which can hinder the interaction between ACE2 and Covid
protein. According to that report, the MM/GBSA scores of
FDA approved drugs ranged from 18.563 to 78.259 based
upon different grid sites. Some FDA approved drugs like
Miglitol, Ribavirin, Xanthinol, Lamivudine, Levosalbutamol,
Cangrelor showed MM/GBSA less than 30KJ/mol. Similar
kind of comparison was also done for TMPRSS2 and IL-6
(Durdagi, 2020, Beura & Chetti, 2020). Our study revealed
better MM-GBSA score than some of the approved drugs val-
idating their candidature as a potent therapeutic agent in
post-Covid syndrome.
Thus, two compounds CVN and CBD present in Cannabis
showed considerable affectivity with ACE2, TMPRSS2, IL6
and NRP1 proteins which are mainly hijacked by Covid-19
and are probably the cause of major post-Covid neuro-
degeneration problems. A schematic diagram of the prob-
able mechanism of CBD and CVN has been shown in
(Figure 5).
To date, research data linking the effect of cannabis in
treating the post-Covid-CNS problem is limiting. However,
novel approaches to include CBD in mouthwash and throat
gargling liquids are on the plate since they drastically reduce
the ACE2 level in the oral cavity (Wang et al., 2020). The
main complications in the post-Covid situation are neurode-
generation-related symptoms. In this context, an increase in
neurogenesis may treat the problem. Adult neurogenesis is a
perfect example of brain plasticity modulated through the
endocannabinoid system. It has been reported that
Cannabidiol (CBD)(Wang et al., 2020), a major component of
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS 3
Cannabis acts directly on spatial learning and adult neuro-
genesis. They enhance neurogenesis without impairing learn-
ing ability. Moreover, the brain Renin-angiotensin system
(RAS) is well known for its involvement in brain functions
and disorders. Excessive brain angiotensin-converting
enzyme (ACE) is associated with oxidative stress, apoptosis
and neuroinflammation leading to neurodegeneration. From
our docking study, we found CBD can bind to ACE2 at its
active site with a binding energy of 8.9 kcal/mol acting as a
repressor of that protein. This down-regulation of ACE2 pre-
vents disease progression. Moreover, cannabis contained sev-
eral terpenes that may act synergistically with CBD to
increase its potency. Thus terpenes along with CBD show an
entourageeffect where, the whole plant extract can be
more beneficial than individual compounds (Wang
et al., 2020).
The second major target protein in this study as obtained
from the docking experiment was Il-6. This cytokine
Interleukin 6 plays a pivotal role in the pathogenesis of
inflammatory diseases along with the maintenance of neural
homeostasis (Kovalchuk et al., 2020). Profound neuropatho-
logical disorders like multiple sclerosis, Parkinsons and
Alzheimers disease have been reported to have higher
expression of IL-6. Moreover, in Covid condition, the overex-
pression of Il-6 in neurons and astrocytes has already been
reported. Interestingly, it can be assumed that in post Covid
condition when CoV-2 infiltration is absent in CNS, these
aforementioned cytokines can be involved in the host anti-
Figure 1. (a) Molecular docking of ACE2 protein with CBD. (b) RMSD plot comparison between the protein and docked complex. (c) RMSF plot comparison
between the protein and docked complex. The red color indicates the protein and black indicates the docked complex.
4 I. SARKAR ET AL.
viral response by over-stimulating the host immune system
leading to inflammation (Kovalchuk et al., 2020). This can dir-
ectly cause several neuropsychiatric symptoms through neu-
roinflammatory responses along with compromised blood-
brain interface integrity (BBI) leading to the transmigration of
peripheralimmune cells into CNS along with disruption of
neurotransmission(Kovalchuk et al., 2020). As per our result,
CBD binds to IL-6 with a binding energy of 8.2 kcal/mol
and exerts an inhibitory action. Inhibition leads to downregu-
lation of Il-6 and thus the CNS- neurotoxicity produced by
IL6 can be altered through Cannabis (Kovalchuk et al., 2020).
Along with ACE2 and IL6, TMPRSS2 serine protease also
acts as a major target in post-Covid treatment. This protein
is attacked by spike proteins of SARS-CoV2 and thus crucial
for viral entrance to the host system (Palit et al., 2020).
Overexpression of these transmembrane serine proteases is
also related to post Covidneuro-degenerative disorders. Thus,
inhibitors of TMPRSS2 will not only help in the prevention of
Covid-19 but also deal with post-Covid CNS problems (Palit
et al., 2020). CVN was found to be bound to this protein
with high efficiency downregulating its expression. This
result was also supported through one of the previous stud-
ies regarding the effect of Cannabis on TMPRSS2 protein
(Palit et al., 2020). A similar effect can also be obtained by
CVN on NRP1 protein. Thus, both CBD and CVN can act dir-
ectly on the aforementioned proteins which are crucial for
the Covid-19 related neuro-degeneration problem.
We may propose a two-fold action of Cannabis derived
compounds. First, they interact with the same amino acid
residues of target proteins with which covid protein residues
can also bind. Thus, there may be a competition between
the covid proteins and CBD/CVN for the same binding site.
This competition possibly would force the covid residues to
detach from the proteins and binding of CBD/CVN to the tar-
get proteins. Thus, these phytochemicals will eventually be
freedup the receptor proteins from Covid particles. Second,
Figure 2. (a) Molecular docking of Il-6 protein with CBD. (b) RMSD plot comparison between the protein and docked complex. (c) RMSF plot comparison between
the protein and docked complex. The red color indicates the protein and black indicates the docked complex.
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS 5
Cannabis derived compounds generally downregulate ACE2,
Il-6 and transmembrane serine protease family proteins.
Since in the post-Covid stage all these proteins remain in
upregulated form, an overall downregulation of them via
CBD/CVN will definitely revert back our neural system to nor-
mal homeostasis giving relief from post-Covid neurodegener-
ative symptoms. However, the dosage of both CBD and CVN
should be optimized and are open for clinical trials.
Root-mean-square deviation (RMSD)
Root-mean-square deviation (RMSD) value of proteins and
docked protein-ligand complexes were investigated to scru-
tinize the changes in the molecular dynamics of protein
along with their conformational stability. This is a popular
quantitative measure of similarities among protein structures.
The lower the RMSD value the better is the new configur-
ation as compared with the actual protein structure. In lig-
and-protein interaction, generally, the RMSD values of the
carbon backbone are compared between the actual protein
and the protein-ligand complex. Lesser difference between
RMSD of actual protein and protein-ligand complex is better.
In our study, RMSD values of C-alpha atoms were plotted
against time. The RMSD value of 6CS2 ranged from 1.8-4.5
over a 100 ns time scale. The range deviated a little for the
6CS2-CBD complex (1.8-2.5). This clearly indicated that the
binding of CBD to 6CS2 has not drastically changed the pro-
tein configuration and its functionality. Similarly, the RMSD
value of 1ALU ranged from 1.8-3.9 whereas the value was
1.8-2.0 for the 1ALU-CBD complex. RMSD values of 3NPS and
7B6P varied from 1.8-2.8 and 2.5-4.1 respectively however,
Figure 3. (a) Molecular docking of TMPRSS2 protein with CVN. (b) RMSD plot comparison between the protein and docked complex. (c) RMSF plot comparison
between the protein and docked complex. The red color indicates the protein and black indicates the docked complex.
6 I. SARKAR ET AL.
the 3NPS-CVN complex showed a variation from 1.8-2.3. The
backbone RMSD of 7B6P-CVN was found to be ranging from
2.5-3.7 over 100 ns time scale. This analysis (Figures 1b, 2b,
3b, and 4b) revealed that the protein-ligand complex did not
distort the structural conformation of the actual protein to a
larger extent strengthening the candidature of CBD and CVN
as post-Covid-CNS treatment.
Root mean square fluctuation
RMSF plot is useful in depicting residues that have experi-
enced major fluctuations during the molecular dynamics
simulation (Muralidharan et al., 2020). RMSF for C-alpha
atoms of each amino acid and was plotted against the num-
ber of residues. RMSF values for 6CS2, 1ALU, 3NPS and 7B6P
over 100 ns time scale fluctuated from 1.3-3.2, 0.2-0.45, 0.1-
0.4 and 0.1-0.42 respectively. The RMSF values of respective
protein-ligand complexes i.e. 6CS2-CBD, 1ALU-CBD, 3NPS-
CVN and 7B6P-CVN were 1.5-3.1, 0.2-0.4, 0.1-0.28, 0.1-0.3
respectively.
These plots revealed a similar fluctuation pattern for both
proteins and protein-ligand complexes for all four simulation
studies (Figures 1c, 2c,3c, and 4c). We can predict the con-
formational stability of the protein-ligand complex if there
are no considerable changes before and after MD simulations
Figure 4. (a) Molecular docking of NRP1 protein with CVN. (b) RMSD plot comparison between the protein and docked complex. (c) RMSF plot comparison
between the protein and docked complex. The red color indicates the protein and black indicates the docked complex.
Table 1. MM-GBSA calculation of all protein ligand complexes
Compound ACE2 TMPRSS2 NRP1 interleukin (IL)-6
Cannabivarin 50.23/50.21 48.24/48.41 31.02/30.28 31.03/31.05
Cannabidiol 43.2/42.98 31.47/30.95 34.28/33.85 37.12/37.93
The first value before /is the value for the first simulation run and the value after /is from the second time simulation run.
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS 7
(Khan et al., 2020). In this study, 100 ns MD simulation of all
four docked complexes revealed no major changes in the
binding pattern. RMSF analysis indicated that binding of
select ligands with considered proteins showed no major
complications in terms of flexibility of protein and structural
conformations thus reinforcing the effect of both CBD and
CVN in post-Covid care.
Conclusion
The present outbreak of SARS-CoV-2, an influenza virus with
neurotropic potential, emerged as neurological manifesta-
tions in a large proportion of the affected individuals as
post-Covid symptoms throughout the world. Disorders of the
central and peripheral nervous system have become com-
mon after the Covid treatment. People with these severe
complications are most likely elderly with medical comorbid-
ities, especially hypertension and other vascular risk factors.
In this consequence, we tried to come up with some solu-
tions to post Covid CNS symptoms. In silico screening of CBD
and CVN from Cannabis has revealed potential therapeutic
properties against these post-Covid neural complications.
Moreover, some previous studies have focused on the effect
of caffeine on Cannabis effectively. We have already started
work to reveal the synergistic effects of CBD and caffeine in
the post-Covid-CNS spasm as our future aspect of research.
Till now, there is no specific treatment therapy for the post-
Covid CNS syndrome hence we have focused on the post-
Covid syndromes in this study. However, the present study is
completely based on in silico screening and dynamic. The
optimal dosage of these compounds has to be determined
in the future through proper clinical trials.
Figure 5. Schematic representation of the activity of CBD and CVN in post-Covid CNS treatment. Blue, Orange and Pink colored transmembrane protein represents
ACE2 protein, TMPRSS2 and NRP1 protein respectively. The small blue-colored protein in the cell interior represents IL-6. Two-fold mechanism of CBD/CVN has
been hypothesized over here. After Covid treatment the considered target proteins remain over expressed possible due to residual Covid proteins (designated by
fraction of Covid virus). CBD/CVN cope with those binding sites of receptor proteins resulting into forced detachment of Covid residues from target proteins. After
binding of CBD/CVN to receptors they downregulate them helping in reversal of neural homeostasis restoring normal brain functionality.
8 I. SARKAR ET AL.
Authorscontributions
AS, IS, GS conceived the idea. IS, GS and SB designed and
executed the experiments and draft the manuscripts. IS exe-
cuted major docking experiments, AS, MB and IS corrected
the paper. All the authors have read and approved
the article.
Acknowledgements
The financial help provided by the Department of Agriculture, Govt. of
West Bengal, for establishing the Biswa Bangla Genome Centre is
acknowledged. We also thank Dr. St
ephane Abel of Centre dEtudes de
Saclay for assisting in molecular dynamics and simulation of some Covid
related proteins.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work is partially funded by the Department of Biotechnology, Govt.
of West Bengal.
ORCID
Indrani Sarkar http://orcid.org/0000-0002-5829-4510
Arnab Sen http://orcid.org/0000-0002-2079-5117
References
Al-Khafaji, K., Al-Duhaidahawi, D., & Taskin Tok, T. (2020). Using inte-
grated computational approaches to identify safe and rapid treatment
for SARS-CoV-2. Journal of Biomolecular Structure and Dynamics,19.
Behl, T., Kaur, I., Bungau, S., Kumar, A., Uddin, M. S., Kumar, C., Pal, G.,
Shrivastava, K., Zengin, G., & Arora, S. (2020). The dual impact of ACE2
in COVID-19 and ironical actions in geriatrics and pediatrics with pos-
sible therapeutic solutions. Life Sciences,257, 118075. https://doi.org/
10.1016/j.lfs.2020.118075
Beura, S., & Chetti, P. (2020). In-silico strategies for probing chloroquine-
based inhibitors against SARS-CoV-2. Journal of Biomolecular Structure
and Dynamics,113.
Bonaventura, A., Vecchi
e, A., Wang, T. S., Lee, E., Cremer, P. C., Carey, B.,
Rajendram, P., Hudock, K. M., Korbee, L., Van Tassell, B. W., Dagna, L.,
& Abbate, A. (2020). Targeting GM-CSF in COVID-19 pneumonia:
Rationale and strategies. Frontiers in Immunology,11, 1625. https://
doi.org/10.3389/fimmu.2020.01625
Cao, X. (2020). COVID-19: Immunopathology and its implications for ther-
apy. Nature Reviews. Immunology,20(5), 269270. https://doi.org/10.
1038/s41577-020-0308-3
Clerkin, K. J., Fried, J. A., Raikhelkar, J., Sayer, G., Griffin, J. M., Masoumi,
A., Jain, S. S., Burkhoff, D., Kumaraiah, D., Rabbani, LRoy., Schwartz, A.,
& Uriel, N. (2020). COVID-19 and cardiovascular disease. Circulation,
141(20), 16481655. https://doi.org/10.1161/CIRCULATIONAHA.120.
046941
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool
to evaluate pharmacokinetics, drug-likeness and medicinal chemistry
friendliness of small molecules. Scientific Reports,7, 42717. https://doi.
org/10.1038/srep42717
Davido, B., Seang, S., Tubiana, R., & de Truchis, P. (2020). Post-COVID-19
chronic symptoms: A postinfectious entity? Clinical Microbiology and
Infection: The Official Publication of the European Society of Clinical
Microbiology and Infectious Diseases,26(11), 14481449. https://doi.
org/10.1016/j.cmi.2020.07.028
Durda
gi, S. (2020). Virtual drug repurposing study against SARS-CoV-2
TMPRSS2 target. Turkish Journal of Biology ¼Turk Biyoloji Dergisi,44(3),
185191. https://doi.org/10.3906/biy-2005-112
Isahq, M. S., Afridi, M. S., Ali, J., Hussain, M. M., Ahmad, S., & Kanwal, F.
(2015). Proximate composition, phytochemical screening, GC-MS stud-
ies of biologically active cannabinoids and antimicrobial activities of
Cannabis indica. Asian Pacific Journal of Tropical Disease,5(11),
897902. https://doi.org/10.1016/S2222-1808(15)60953-7
Kar, P., Sharma, N. R., Singh, B., Sen, A., & Roy, A. (2020a). Natural com-
pounds from Clerodendrum spp. as possible therapeutic candidates
against SARS-CoV-2: An in silico investigation. Journal of Biomolecular
Structure and Dynamics,112.
Kar, P., Kumar, V., Vellingiri, B., Sen, A., Jaishee, N., Anandraj, A.,
Malhotra, H., Bhattacharyya, S., Mukhopadhyay, S., Kinoshita, M., &
Govindasamy, V. (2020b). Anisotine and amarogentin as promising
inhibitory candidates against SARS-CoV-2 proteins: A computational
investigation. Journal of Biomolecular Structure and Dynamics,111.
Khan, M. T., Ali, A., Wang, Q., Irfan, M., Khan, A., Zeb, M. T., Zhang, Y.-J.,
Chinnasamy, S., & Wei, D. Q. (2020). Marine natural compounds as
potents inhibitors against the main protease of SARS-CoV-2. A
molecular dynamic study. Journal of Biomolecular Structure and
Dynamics,2020,111. https://doi.org/10.1080/07391102.2020.1769733
Kovalchuk, A., Rodriguez-Juarez, R., Ilnytskyy, S., Li, D., Wang, B.,
Kovalchuk, I., & Kovalchuk, O. (2020). Fighting the storm: novel anti-
TNFaand anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19.
Lin, Q., Zhao, S., Gao, D., Lou, Y., Yang, S., Musa, S. S., Wang, M. H., Cai,
Y., Wang, W., Yang, L., & He, D. (2020). A conceptual model for the
outbreak of Coronavirus disease 2019 (COVID-19) in Wuhan, China
with individual reaction and governmental action. International
Journal of Infectious Diseases: IJID: Official Publication of the
International Society for Infectious Diseases,93, 211216. https://doi.
org/10.1016/j.ijid.2020.02.058
Marshall, M. (2020). How COVID-19 can damage the brain. Nature,
585(7825), 342343. https://doi.org/10.1038/d41586-020-02599-5
Mittal, L., Kumari, A., Srivastava, M., Singh, M., & Asthana, S. (2020).
Identification of potential molecules against COVID-19 main protease
through structure-guided virtual screening approach. Journal of
Biomolecular Structure and Dynamics,119.
Muralidharan, N., Sakthivel, R., Velmurugan, D., & Gromiha, M. M. (2020).
Computational studies of drug repurposing and synergism of lopina-
vir, oseltamivir and ritonavir binding with SARS-CoV-2 Protease
against COVID-19. Journal of Biomolecular Structure and Dynamics,16,
16. https://doi.org/10.1080/07391102.2020.1752802
Palit, P., Chattopadhyay, D., Thomas, S., Kundu, A., Kim, H. S., & Rezaei,
N. (2020). Phytopharmaceuticals mediated Furin and TMPRSS2 recep-
tor blocking: Can it be a potential therapeutic option for Covid-19?
Phytomedicine, 153396. https://doi.org/10.1016/j.phymed.2020.153396
Prajapat, M., Shekhar, N., Sarma, P., Avti, P., Singh, S., Kaur, H.,
Bhattacharyya, A., Kumar, S., Sharma, S., Prakash, A., & Medhi, B.
(2020). Virtual screening and molecular dynamics study of approved
drugs as inhibitors of spike protein S1 domain and ACE2 interaction
in SARS-CoV-2. Journal of Molecular Graphics & Modelling,101, 107716.
https://doi.org/10.1016/j.jmgm.2020.107716
Pronk, S., P
all, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., Shirts,
M. R., Smith, J. C., Kasson, P. M., van der Spoel, D., Hess, B., & Lindahl,
E. (2013). GROMACS 4.5: A high-throughput and highly parallel open
source molecular simulation toolkit. Bioinformatics (Oxford, England),
29(7), 845854. https://doi.org/10.1093/bioinformatics/btt055
Raphael, K. G. (2020). Concerns raised by publication of Antonini et al.,
"Outcome of Parkinson Disease patients affected by Covid-19".
Movement Disorders: Official Journal of the Movement Disorder Society,
35(8), 1297. https://doi.org/10.1002/mds.28180
Russo, E. B., Guy, G. W., & Robson, P. J. (2007). Cannabis, pain, and sleep:
Lessons from therapeutic clinical trials of Sativex, a cannabis-based
medicine. Chemistry & Biodiversity,4(8), 17291743. https://doi.org/10.
1002/cbdv.200790150
Sarkar, I., & Sen, A. (2020). In silico screening predicts common cold drug
Dextromethorphan along with Prednisolone and Dexamethasone can
be effective against novel Coronavirus disease (COVID-19). Journal of
Biomolecular Structure and Dynamics,15.
JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS 9
Sarma, P., Kaur, H., Kumar, H., Mahendru, D., Avti, P., Bhattacharyya, A.,
Prajapat, M., Shekhar, N., Kumar, S., Singh, R., & Singh, A. (2020).
Virological and clinical cure in COVID-19 patients treated with hydrox-
ychloroquine: a systematic review and meta-analysis. Journal of
Medical Virology,92(7), 776785.
Singh, D. D., Han, I., Choi, E. H., & Yadav, D. K. (2020). Immunopathology,
host-virus genome interactions, and effective vaccine development in
SARS-CoV-2. Computational and Structural Biotechnology Journal,18,
37743787. https://doi.org/10.1016/j.csbj.2020.11.011
Singh, D. D., Han, I., Choi, E. H., & Yadav, D. K. (2020a). Recent advances
in pathophysiology, drug development and future perspectives of
SARS-CoV-2. Frontiers in Cell and Developmental Biology,8, 580202.
https://doi.org/10.3389/fcell.2020.580202
Tayyab, M., & Shahwar, D. (2015). GCMS analysis of Cannabis sativa L.
from four different areas of Pakistan. Egyptian Journal of Forensic
Sciences,5(3), 114125. https://doi.org/10.1016/j.ejfs.2014.07.008
Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and
accuracy of docking with a new scoring function, efficient optimiza-
tion, and multithreading. Journal of Computational Chemistry,31(2),
455461. https://doi.org/10.1002/jcc.21334
Troyer, E. A., Kohn, J. N., & Hong, S. (2020). Are we facing a crashing
wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric
symptoms and potential immunologic mechanisms. Brain, Behavior,
and Immunity,87,3439. https://doi.org/10.1016/j.bbi.2020.04.027
Wang, B., Kovalchuk, A., Li, D., Ilnytskyy, Y., Kovalchuk, I., & Kovalchuk, O.
(2020). In search of preventative strategies: Novel anti-inflammatory
high-CBD cannabis sativa extracts modulate ACE2 expression in Covid-
19 gateway tissues.
Wijeratne, T., & Crewther, S. (2020). Post-COVID 19 Neurological
Syndrome (PCNS); a novel syndrome with challenges for the global
neurology community. Journal of the Neurological Sciences,419,
117179. https://doi.org/10.1016/j.jns.2020.117179
Yin, Y., Zhou, Z., Liu, W., Chang, Q., Sun, G., & Dai, Y. (2017). Vascular
endothelial cells senescence is associated with NOD-like receptor fam-
ily pyrin domain-containing 3 (NLRP3) inflammasome activation via
reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP)
pathway. The International Journal of Biochemistry & Cell Biology,84,
2234. https://doi.org/10.1016/j.biocel.2017.01.001
Zhang, M. Q., & Wilkinson, B. (2007). Drug discovery beyond the rule-of-
five.Current Opinion in Biotechnology,18(6), 478488. https://doi.org/
10.1016/j.copbio.2007.10.005
10 I. SARKAR ET AL.
... Thus, in an in silico docking study, both CBD and THC revealed a moderate inhibitory effect against human ACE2 and a strong (CBD) and moderate (THC) inhibitory effect on the main virus protease [101]. In another in silico study, CBD and cannabivarin were the most potent among 8 compounds derived from the cannabis plant to inhibit ACE2 [102]. Moreover, CBD decreased ACE2 expression in human 3D tissue models of oral, airway, and intestinal tissues (that serve as routes for the invasion of SARS-CoV-2) [103] and in human cell lines ( [31,105]; Table 4). ...
... It should be highlighted that, as shown in Table 4, cannabis extracts, including various phytocannabinoids and terpenes, not only down-regulate ACE2 but can also suppress transmembrane serine protease 2 (TMPRSS2; another virus entry site into the cytoplasm of host cells) [31,103,106], main viral protease [101], neuropilin 1 (NRP1) [102], or inflammationpromoting agents such as IL-6 or IL-8 [31,102,104], CCL2 [104] or cyclooxygenase-2 [31]. However, one should keep in mind that CBD itself is characterized by a bell-shaped doseresponse curve associated with a narrow therapeutic window, which makes its effective clinical use difficult. ...
... It should be highlighted that, as shown in Table 4, cannabis extracts, including various phytocannabinoids and terpenes, not only down-regulate ACE2 but can also suppress transmembrane serine protease 2 (TMPRSS2; another virus entry site into the cytoplasm of host cells) [31,103,106], main viral protease [101], neuropilin 1 (NRP1) [102], or inflammationpromoting agents such as IL-6 or IL-8 [31,102,104], CCL2 [104] or cyclooxygenase-2 [31]. However, one should keep in mind that CBD itself is characterized by a bell-shaped doseresponse curve associated with a narrow therapeutic window, which makes its effective clinical use difficult. ...
Article
Full-text available
This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.
... Thus, the interest in cannabinoids to diminish the effects of the cytokine storm as a serious manifestation of SARS-CoV-2 infection is pronounced, of late. In molecular docking studies of cannabinoids and their binding to ACE2, TMPSS2, IL-6 and the histone chaperone NRP1, CBD and cannabivarin (CBV, Fig. 6) demonstrated significant binding affinity with binding free energies between −8.2 and −8.9 kcal/mol [80]. Binding of the cannabinoid with the these target proteins results in downregulation of corresponding activity and an implied competition between binding of cannabinoids and the endogenous ligand [80]. ...
... In molecular docking studies of cannabinoids and their binding to ACE2, TMPSS2, IL-6 and the histone chaperone NRP1, CBD and cannabivarin (CBV, Fig. 6) demonstrated significant binding affinity with binding free energies between −8.2 and −8.9 kcal/mol [80]. Binding of the cannabinoid with the these target proteins results in downregulation of corresponding activity and an implied competition between binding of cannabinoids and the endogenous ligand [80]. ...
Article
Full-text available
During the COVID-19 pandemic lasting now for well more than a year, nearly 247 million cases have been diagnosed and over 5 million deaths have been recorded worldwide as of November 2021. The devastating effects of the SARS-CoV-2 virus on the immune system lead to the activation of signaling pathways involved in inflammation and the production of inflammatory cytokines. SARS-CoV-2 displays a great deal of homology with other coronaviruses, especially SARS-CoV and MERS-CoV which all display similar components which may serve as targets, namely the Spike (S) protein, the main protease (MPro) which is a chymotrypsin-like protease (CLPro) and RNA-directed RNA polymerase (RdRp). Natural constituents found in traditional herbal medicines, dietary supplements and foods demonstrate activity against SARS-CoV-2 by affecting the production of cytokines, modulating cell signaling pathways related to inflammation and even by direct interaction with targets found in the virus. This has been demonstrated by the application of fluorescence resonance energy transfer (FRET) experiments, assays of cytopathic effect (CPE) and in silico molecular docking studies that estimate binding strength. Glycyrrhizin, flavonoids such as quercetin, kaempferol and baicalein, and other polyphenols are the most common constituents found in Traditional Chinese Medicines that modulate inflammation and cell signaling pathways, and bind viral targets demonstrating valuable effects against SARS-CoV-2. However, the bioavailability of these natural products and their dependence on each other in extracts make it difficult to assess their actual utility in the treatment of COVID-19. Therefore, more can be learned through rational drug design based on natural products and from well-designed clinical trials employing specific doses of standardized combinations.
... The use of the flavonoid luteolin, which inhibits the pro-inflammatory cascade of mast cells and microglia, has been suggested as a potential treatment (Theoharides et al. 2021). From simulation and molecular docking studies, cannabis has been shown to have the potential to bind and downregulate central nervous system proteins linked to symptoms of long-COVID-19 (Sarkar et al. 2021). Methylene blue, due to its mitochondrial protective effects, has been suggested as a possible therapy against neurological deterioration due to SARS-CoV-2 (Magoon et al. 2021). ...
Article
Full-text available
SARS-CoV-2 pandemic has caused a collapse of the world health systems. Now, vaccines and more effective therapies have reversed this crisis but the scenario is further aggravated by the appearance of a new pathology, occurring as SARS-CoV-2 infection consequence: the long-COVID-19. This term is commonly used to describe signs and symptoms that continue or develop after acute infection of COVID-19 up to several months. In this review, the consequences of the disease on mental health and the neurological implications due to the long-COVID are described. Furthermore, the appropriate nutritional approach and some recommendations to relieve the symptoms of the pathology are presented. Data collected indicated that in the next future the disease will affect an increasing number of individuals and that interdisciplinary action is needed to counteract it.
... In addition to examining the effects of expression of these genes alone, we have also investigated effects of combining their expression with cannabidiol (CBD). CBD is the major non-psychotropic phytocannabinoid constituent of Cannabis sativa [43], and has been hypothesized as a potential therapeutic in COVID-19 [44,45]. Evidence from the literature supports that CBD has anti-inflammatory properties [46] and may have a role as a potential protective agent or therapeutic in cells experiencing metabolic distress, such as that associated with viral infection [43,47]. ...
Article
Full-text available
Aims To study effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD). Main methods HEK293 cells transfected with plasmids expressing control vector, ORF8, ORF10, or M protein were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without CBD. Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection. Key findings Reduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1–2 μM CBD treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2′-5′-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. CBD similarly enhanced the cellular anti-viral response to Poly (I:C). Significance Our results demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of CBD. Thus, CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.
... Additionally, the present study recommends the use of anti-inflammatory and anti-oxidant drugs against COVID-19-associated complications. Moreover, the in silico studies conducted on COVID-19 suggested that cannabivarin (CVN) and cannabidiol (CBD) obtained from cannabis can bind to the ACE2, interleukin-6, and transmembrane serine protease, which are significantly involved in post-COVID-19 complications [199]. Similarly, another in silico study has suggested that amongst the reported molecules used against viral infection, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed binding to COVID-19 enzyme. ...
Article
Full-text available
The novel coronavirus (2019-nCoVCOVID-19) belongs to the Beta coronavirus family, which contains MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV (severe acute respiratory syndrome coronavirus). SARS-CoV-2 activates the innate immune system, thereby activating the inflammatory mechanism, causing the release of inflammatory cytokines. Moreover, it has been suggested that COVID-19 may penetrate the central nervous system, and release inflammatory cytokines in the brains, inducing neuroinflammation and neurodegeneration. Several links connect COVID-19 with Alzheimer’s disease (AD), such as elevated oxidative stress, uncontrolled release of the inflammatory cytokines, and mitochondrial apoptosis. There are severe concerns that excessive immune cell activation in COVID-19 may aggravate the neurodegeneration and amyloid-beta pathology of AD. Here, we have collected the evidence, showing the links between the two diseases. The focus has been made to collect the information on the activation of the inflammation, its contributors, and shared therapeutic targets. Furthermore, we have given future perspectives, research gaps, and overlapping pathological bases of the two diseases. Lastly, we have given the short touch to the drugs that have equally shown rescuing effects against both diseases. Although there is limited information available regarding the exact links between COVID-19 and neuroinflammation, we have insight into the pathological contributors of the diseases. Based on the shared pathological features and therapeutic targets, we hypothesize that the activation of the immune system may induce neurological disorders by triggering oxidative stress and neuroinflammation.
... The cannabis derivatives cannabidiol and cannabivarin have been suggested to have the potential to bind to and downregulate central nervous system proteins related to long-COVID symptoms. These compounds have not been tested in clinical studies [116]. Methylene blue has been suggested as a possible therapy for neurocognitive impairment in long COVID due to its mitochondrial protective effects [117]. ...
Article
Scope The aim of these guidelines is to provide evidence-based recommendations for assessment and management of individuals with persistent symptoms after acute COVID-19 infection, and provide a definition for this entity, termed “long COVID”. Methods We performed a search of the literature on studies addressing epidemiology, symptoms, assessment, and treatment of long COVID. The recommendations were grouped by these headings and by organ systems for assessment and treatment. An expert opinion definition of long COVID is provided. Symptoms were reviewed by a search of the available literature. For assessment recommendations, we aimed to perform a diagnostic meta-analysis, but no studies provided relevant results. For treatment recommendations we performed a systematic review of the literature in accordance with the PRISMA statement. We aimed to evaluate patient-related outcomes, including quality of life, return to baseline physical activity, and return to work. Quality assessment of studies included in the systematic review is provided according to study design. Recommendations Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high quality prospective clinical studies/trials, including a control group, to further evaluate assessment and management of individuals with persistent symptoms of COVID-19.
... An in silico study revealed that caflanone has affinity to the viral spike protein, protease sites and helicase on the ACE2 receptor, and compared to chloroquine it showed higher binding energy with the spike protein, helicase and protease [184]. An MD simulation and docking study showed that the binding of CBD and cannabivarin (CBV) with ACE2, TMPRSS2, IL-6 and NRP1 (neuropilin 1) occurs, meaning that cannabinoids may be beneficial for CNS related post-COVID symptoms [191]. Neuropilin 1 is a protein which is encoded in humans (NRP1 gene), can interact with SARS-CoV-2 S protein and promote virus entry [192]. ...
Article
Full-text available
Abstract: Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coron-avirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO's current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants.
Article
The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of 7 phytocannabinoids and 4 terpenes were considered. On the side of ligand‐based virtual screening, physico‐chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug‐like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure‐based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (‐9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted. Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration.
Article
Full-text available
One-fifth of COVID-19 patients suffer a severe course of COVID-19 (SARS-CoV-2) infection; however, the specific causes remain unclear. Despite numerous papers that have been flooded in different scientific journals clear clinical picture of COVID-19 aftermath persists to remain fuzzy. The survivors of severe COVID-19infection having defeated the virus are just the starting of an uncharted recovery path. Currently, there is no drug available that is safe to consume to combat this pandemic. However, researchers still struggling to find specific therapeutic solutions. The present study employed an in silico approach to assessing the inhibitory potential of the phytochemicals obtained from GC-MS analysis of Citrus macroptera against inflammatory proteins like COX-2, NMDAR and VCAM-1 which remains in a hyperactive state even after a patient is fully cured of this deadly mRNA virus. An extensive molecular docking investigation of the phyto-compounds at the active binding pockets of the inflammatory proteins revealed the promising inhibitory potential of the phytochemicals. Reasonable physicochemical attributes of the compounds following Lipinski’s rule of five, VEBER and PAINS analysis further established them as potential therapeutic candidates against aforesaid inflammatory proteins. MM-GBSA binding free energy estimation revealed that Limonene was the most promising candidate displaying the highest binding efficacy with the concerned VCAM-1 protein included in the present analysis. An interesting finding is the phytochemicals exhibited better binding energy scores with the concerned COX-2, VCAM-1 and NMDA receptor proteins than the conventional drugs that are specifically targeted against them. Our in silico results suggest that all the natural phyto-compounds derived from C. macroptera could be employed in Post covid inflammation complexities after appropriate pre-clinical and clinical trials for further scientific validation. Communicated by Ramaswamy H. Sarma
Article
Full-text available
Coronaviruses are a group of enveloped RNA viruses that are diversely found in humans and now declared a global pandemic by the World Health Organization in March 2020. The population's susceptibility to these highly pathogenic coronaviruses has contributed to large outbreaks, evolved into public health events, and rapidly transmitted globally. Thus, there is an urgent need to develop effective therapies and vaccines against this disease. In the primary stage of severe acute respiratory syndrome coronavirus (SARS-COV-2) infection, the signs and symptoms are nonspecific, and many more cases have been observed than initially expected. Genome sequencing is performed regularly to identify genetic changes to SARS-COV-2, and vaccine development is focused on manufacture, production, and based on specific problems, and very few are available on recent developments in the prevention of outbreaks. The aim of this review article to explore recent updates on SARS-COV-2 in the context of pathogenesis during disease progression, and innate acquired mechanisms of defense, This includes advances in diagnostics, susceptibility, and severity of host-virus genome interactions, modes of transmission, active compounds being used in pre-clinical and clinical trials for the treatment of patients, vaccine developments, and the effectiveness of SARS-COV-2 prevention and control measures. We have summarized the importance of pathophysiology immune response, Diagnostics, vaccine development currently approaches explored for SARS-COV-2.
Article
Full-text available
The ongoing outbreak of Coronavirus disease 2019 (COVID-19) is a matter of great concern. Although the mortality rate caused by this virus is less than that of SARS and MERS, it is showing higher efficacy in terms of human-to-human transmission. Several strategies have been taken by scientists and researchers worldwide to combat this virus. Numerous phytochemicals and synthesized chemicals are under incessant inspection to obtain a potent anti-covid drug. Since, till now no precise therapy is available for covid patients, researchers are trying to categorize all possible anti-covid substances. Repurposing of drugs and combined drug therapy are becoming popular in treating such viral diseases. In this study, we are proposing the repurposing of three chemicals-Dextromethorphan, Prednisolone and Dexamethasone as anti-covid agents. We have used the tertiary structure of Coronavirus main protease (Mpro) with PDB ID 6LU7 as the target protein in this analysis. Molecular docking and dynamics study further revealed their synergistic effect against the COVID-19 protease protein. Communicated by Ramaswamy H. Sarma
Article
The coronavirus (SARS-CoV-2) pandemic is a rapidly transmitting and highly pathogenic disease. The spike protein of SARS-CoV-2 binds to the surface of angiotensin-converting enzyme-2 (ACE2) receptors along the upper respiratory tract and intestinal epithelial cells. SARS-CoV-2 patients develop acute respiratory distress, lymphocytic myocarditis, disseminated intravascular coagulation, lymphocytic infiltration, and other serious complications. A SARS-CoV-2 diagnosis is conducted using quantitative reverse-transcription PCR and computed tomography (CT) imaging. In addition, IgM or IgG antibodies are used to identify acute and convalescent illness. Recent clinical data have been generated by health workers and researchers and have shown that there is an urgent requirement in the effective clinical and treatment of patients, as well as other developments for dealing with SARS-CoV-2 infection. A broad spectrum of clinical trials of different vaccines and drug treatment has been evaluated for use against SARS-CoV-2. This review includes the emergence of SARS-CoV-2 pneumonia as a way to recognize and eliminate any barriers that affect rapid patient care and public health management against the SARS-CoV-2 epidemic based on the natural history of the disease, its transmission, pathogenesis, immune response, epidemiology, diagnosis, clinical presentation, possible treatment, drug and vaccine development, prevention, and future perspective.
Article
Background: Currently, novel coronavirus disease (Covid-19) outbreak creates global panic across the continents, as people from almost all countries and territories have been affected by this highly contagious viral disease. The scenario is deteriorating due to lack of proper & specific target-oriented pharmacologically safe prophylactic agents or drugs, and or any effective vaccine. drug development is urgently required to back in the normalcy in the community and to combat this pandemic. Purpose: Thus, we have proposed two novel drug targets, Furin and TMPRSS2, as Covid-19 treatment strategy. We have highlighted this target-oriented novel drug delivery strategy, based on their pathophysiological implication on SARS-CoV-2 infection, as evident from earlier SARS-CoV-1, MERS, and influenza virus infection via host cell entry, priming, fusion, and endocytosis. STUDY DESIGN & METHODS: An earlier study suggested that Furin and TMPRSS2 knockout mice had reduced level of viral load and a lower degree of organ damage such as the lung. The present study thus highlights the promise of some selected novel and potential anti-viral Phytopharmaceutical that bind to Furin and TMPRSS2 as target. Result: Few of them had shown promising anti-viral response in both preclinical and clinical study with acceptable therapeutic safety-index. Conclusion: Hence, this strategy may limit life-threatening Covid-19 infection and its mortality rate through nano-suspension based intra-nasal or oral nebulizer spray, to treat mild to moderate SARS-COV-2 infection when Furin and TMPRSS2 receptor may initiate to express and activate for processing the virus to cause cellular infection by replication within the host cell and blocking of host-viral interaction.
Preprint
https://wfneurology.org/2020-10-13-twijeratne-pcns?fbclid=IwAR0MaAgHbgwtsGP8rjxceARtwdBQMdVpFoqu8s5X_GKTZx_91DxHgJDa0LM
Article
Some people who become ill with the coronavirus develop neurological symptoms. Scientists are struggling to understand why. Some people who become ill with the coronavirus develop neurological symptoms. Scientists are struggling to understand why.
Article
Background The receptor binding domain (RBD) of spike protein S1 domain SARS-CoV-2 plays a key role in the interaction with ACE2, which leads to subsequent S2 domain mediated membrane fusion and incorporation of viral RNA into host cells. In this study we tend to repurpose already approved drugs as inhibitors of the interaction between S1-RBD and the ACE2 receptor. Methods 2456 approved drugs were screened against the RBD of S1 protein of SARS-CoV-2 (target PDB ID: 6M17). As the interacting surface between S1-RBD and ACE2 comprises of bigger region, the interacting surface was divided into 3 sites on the basis of interactions (site 1, 2 and 3) and a total of 5 grids were generated (site 1, site 2, site 3, site 1+site 2 and site 2+site 3). A virtual screening was performed using GLIDE implementing HTVS, SP and XP screening. The top hits (on the basis of docking score) were further screened for MM-GBSA. All the top hits were further evaluated in molecular dynamics studies. Performance of the virtual screening protocol was evaluated using enrichment studies. Result and discussion: We performed 5 virtual screening against 5 grids generated. A total of 42 compounds were identified after virtual screening. These drugs were further assessed for their interaction dynamics in molecular dynamics simulation. On the basis of molecular dynamics studies, we come up with 10 molecules with favorable interaction profile, which also interacted with physiologically important residues (residues taking part in the interaction between S1-RBD and ACE2. These are antidiabetic (acarbose), vitamins (riboflavin and levomefolic acid), anti-platelet agents (cangrelor), aminoglycoside antibiotics (Kanamycin, amikacin) bronchodilator (fenoterol), immunomodulator (lamivudine), and anti-neoplastic agents (mitoxantrone and vidarabine). However, while considering the relative side chain fluctuations when compared to the S1-RBD: ACE2 complex riboflavin, fenoterol, cangrelor and vidarabine emerged out as molecules with prolonged relative stability. Conclusion We identified 4 already approved drugs (riboflavin, fenoterol, cangrelor and vidarabine) as possible agents for repurposing as inhibitors of S1:ACE2 interaction. In-vitro validation of these findings are necessary for identification of a safe and effective inhibitor of S1: ACE2 mediated entry of SARS-CoV-2 into the host cell.
Article
The novel corona virus disease has shaken the entire world with its deadly effects and rapid transmission rates, posing a significant challenge to the healthcare authorities to develop suitable therapeutic solution to save lives on earth. The review aims to grab the attention of the researchers all over the globe, towards the role of ACE2 in COVID-19 disease. ACE2 serves as a molecular target for the SARS-CoV-2, to enter the target cell, by interacting with the viral glycoprotein spikes. However, the complexity began when numerous studies identified the protective response of ACE2 in abbreviating the harmful effects of vasoconstrictor, anti-inflammatory peptide, angiotensin 2, by mediating its conversion to angiotensin-(1–7), which exercised antagonistic actions to angiotensin 2. Furthermore, certain investigations revealed greater resistance among children as compared to the geriatrics, towards COVID-19 infection, despite the elevated expression of ACE2 in pediatric population. Based upon such evidences, the review demonstrated possible therapeutic interventions, targeting both the protective and deleterious effects of ACE2 in COVID-19 disease, primarily inhibiting ACE2-virus interactions or administering soluble ACE2. Thus, the authors aim to provide an opportunity for the researchers to consider RAAS system to be a significant element in development of suitable treatment regime for COVID-19 pandemic.