Preliminary Screening of SARS-CoV-2 Inhibitors 2021

Preliminary Screening of SARS-CoV-2 Inhibitors

Abstract:

The recent outbreak of novel coronavirus disease, COVID‐19 has created a threat to human population
across the world. The unavailability of specific therapeutics and vaccines, demands the sincere efforts in
this direction. Main Proteases of this novel Coronavirus (SARS‐CoV‐2)play critical role during the
disease propagation, and hence represents a crucial target for the drug discovery. Herein, I have applied a
bioinformatics approach for drug repurposing to identify the possible potent inhibitors of SARS‐CoV2 .

A library of FDA approved antiviral compounds, and active phytochemicals were screened using virtual
screening tools like SwissADME , Osiris Property Explorer .After evaluating afrom all the drug likeness
properties , drug score and some Toxicity studies , I got total 9 inhibitors. . My findings suggest that
these small molecules can be used as potential inhibitors against SARS‐CoV2 Main Protease. However,
further investigation and validation of these inhibitors against SARS‐CoV‐2 are needed to claim their
candidacy for clinical trials.

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 Preliminary Screening of SARS-CoV-2 Inhibitors 2021

Introduction:

Preliminary screening is a valuable step, in the detection of the bioactive principles present in
molecule/drug and subsequently may lead to drug discovery and development.

SARS-CoV-2:

In December 2019, reports Trusted Source emerged that a corona virus that specialists had never seen
before in humans had begun to spread among the population of Wuhan, a large city in the Chinese
province of Hubei.From there, the virus spread around the world, leading the World Health Organization
(WHO)Trusted Source to declare this a pandemic in March 2020.

The novel corona virus — called severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) — has
been responsible for millions of infections and more than 2 million deaths. The highest number of deaths
has occurred in the United States.As the pandemic persists, scientists continue to make discoveries that
may help find ways to treat and prevent infection with the virus.

What is SARS-CoV-2?

SARS-CoV-2 is a corona virus that causes corona virus disease 2019 (COVID-19). Corona viruses are a
family of viruses that target and affect mammals’ respiratory systems.

There are four main ranks of corona viruses: alpha, beta, delta, and gamma. Most of these only affect
animals, but some of the alpha and beta types can pass to humans.

Only two corona viruses have previously caused global outbreaks.

The SARS corona virus — responsible for severe acute respiratory syndrome (SARS) — started
spreading in 2002 in China. It mainly affected the populations of mainland China and Hong Kong, and it
disappeared in 2003.

The MERS corona virus — responsible for Middle East respiratory syndrome (MERS) — emerged in
Saudi Arabia in 2012. It has led to 858 deaths since then.

Coronaviruses mainly cause enzootic infections in birds and mammals but in some cases have been
capable of crossing the species barrier and infect humans. Indeed, since 2002, β-corona viruses have
caused three zoonotic outbreaks that are – SARS-CoV,MERS-CoV,and now SARS-CoV-2.

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 Preliminary Screening of SARS-CoV-2 Inhibitors 2021

The SARS-CoV-2 emerged as a zoonotic outbreak at the end of 2019, causing a disease named Covid-19
and being responsible for a pandemic within very few months.

How does it compare with other viruses?

In January 2020 scientists found that, genetically, SARS-CoV-2 is most similar to two bat corona viruses:
bat-SL-CoVZC45 and bat-SL-CoVZXC21. Its genomic sequence is 88% the same as theirs.

The same study showed that the RNA of SARS-CoV-2 is about 79% the same as that of the SARS corona
virus and approximately 50% the same as that of the MERS virus.

Earlier research suggested that pangolins may have been the initial propagators of SARS-CoV-2 among
humans, as the virus’s genomic sequence appears to be 99% the same as that of a corona virus specific to
these animals.

More recent research, however, including a study from October 2020, emphasizes that pangolins, bats,
and other animals are not to blame for epidemics or pandemics affecting humans.

Instead, the real triggers are societal structures that drive human-animal contact. Blaming wildlife can
also lead to unnecessary slaughter and the devastating loss of wildlife biodiversity, the researchers
explain.

Are there any treatments?

There is currently no cure for COVID-19, but some treatments may help manage symptoms.

Most people do not need hospital care but should rest at home and avoid all contact with others.
Symptoms generally improve in about 2 weeks, according to an ongoing survey in the U.K.

People with severe symptoms may need to spend time in a hospital. They may need oxygen therapy and
the use of a mechanical respirator.

In the U.S., two drugs have approval specifically for use against COVID-19 in hospitals. Remdesivir , is
an antiviral drug that may slow the progress of the underlying virus. The other is dexamethasone
(Decadron), a corticosteroid that can help manage inflammation. Antiviral drugs like
Chloroquine,Hydroxychloroquine sulfate are also used.

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 Preliminary Screening of SARS-CoV-2 Inhibitors 2021

What steps are researchers taking?

Over the years, researchers have looked into treatments and vaccines for other corona viruses, and these
may prove useful against the virus that causes COVID-19. A drug that already has approval for other uses
is more likely to be safe.

The FDA have a special emergency program to investigate potential COVID-19 treatments. As of January
2021, they have reviewed more than 400 trials, and more than 591 drug development programs are
underway.

Several large international trials are also ongoing in the search for a treatment. The WHO launched the
largest of these, which is called Solidarity and involves more than 100 countries.

How SARS-CoV-2 infects our cells?

SARS-CoV-2 is an enveloped virus with a positive-sense, single-stranded RNA genome . This virus
enters host cells by receptor-mediated endocytosis. The spike S glycoprotein allows the attachment and
virus internalization to the host cell , by binding to the host ACE2 receptor . Cell entry also depends on
the host cellular serine protease TMPRSS2. SARS-CoV-2 then uses the host cell’s machinery to produce
more viruses. The new viruses are assembled, enveloped and released from the cells via exocytosis, to
infect other cells.

Data sources

In this work, I have collected dataset of SARS-CoV-2 inhibitors, from “https://www.ebi.ac.uk/chembl/”

and first of all classified them on the basis of IC50 value of drug.

ChEMBL is a manually curated database of bioactive molecules with drug-like properties. It brings
together chemical, bioactivity and genomic data to aid the translation of genomic information into
effective new drugs. It is maintained by the European Bioinformatics Institute (EBI), of the European
Molecular Biology Laboratory (EMBL), based at the Wellcome Trust Genome Campus, Hinxton, UK.

So, first of all I classified all the drugs on the basis of their value IC50 value.

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IC50
The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting
a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a
particular inhibitory substance (e.g. drug) is needed to inhibit, in vitro, a given biological process or
biological component by 50%. The biological component could be an enzyme, cell, cell
receptor or microorganism. IC50 values are typically expressed as molar concentration.

IC50 is commonly used as a measure of antagonist drug potency in pharmacological research. IC50 is
comparable to other measures of potency, such as EC50 for excitatory drugs. EC50 represents the dose or
plasma concentration required for obtaining 50% of a maximum effect in vivo.

IC50 can be determined with functional assays or with competition binding assays.

Sometimes, IC50 values are converted to the pIC50 scale.

pIC50 = - log10 (IC50)

Due to the minus sign, higher values of pIC50 indicate exponentially more potent inhibitors. pIC50 is
usually given in terms of molar concentration (mol/L, or M), thus requiring IC50 in units of M.

The IC50 terminology is also used for some behavioral measures in vivo, such as a two bottle fluid
consumption test. When animals decrease consumption from the drug-laced water bottle, the
concentration of the drug that results in a 50% decrease in consumption is considered the IC50 for fluid
consumption of that drug.

In this work , I have considered

IC50 < 1000 nM as - Active.

&

IC50 > 1000 nM as - Inactive.

After classifying them on the basis of IC50 , I had studied Drug Likeness Properties of all active drugs.

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Drug-likeness

Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect
to factors like bioavailability. It is estimated from the molecular structure before the substance is even
synthesized and tested. A druglike molecule has properties such as:

 Solubility in both water and fat, as an orally administered drug needs to pass through the intestinal
lining after it is consumed, be carried in aqueous blood and penetrate the lipid-based cell membrane
to reach the inside of a cell. A model compound for the lipophilic cellular membrane is 1-octanol (a
lipophilic hydrocarbon), so the logarithm of the octanol-water partition coefficient, known as LogP,
is used to predict the solubility of a potential oral drug. This coefficient can be experimentally
measured or predicted computationally, in which case it is sometimes called "cLogP".
 Potency at the biological target. High potency (high value of pIC50) is a desirable attribute in drug
candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration.
When associated with low clearance, high potency also allows for low total dose, which lowers the
risk of idiosyncratic drug reactions.
 Ligand efficiency and lipophilic efficiency.
 Molecular weight: The smaller the better, because diffusion is directly affected. The great majority of
drugs on the market have molecular weights between 200 and 600 Daltons, and particularly
<500;they belong to the group of small molecules.
Based on one definition, a drug-like molecule has a logarithm of partition coefficient (log P) between -0.4
and 5.6, molecular weight 160-480 g/mol, molar refractivity of 40-130, which is related to the volume and
molecular weight of the molecule and has 20-70 atoms.

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration,
and stay there in a bioactive form long enough for the expected biologic events to occur. Drug
development involves assessment of absorption, distribution, metabolism and excretion (ADME)
increasingly earlier in the discovery process, at a stage when considered compounds are numerous but
access to the physical samples is limited. In that context, computer models constitute valid alternatives to
experiments.

On the basis of canonical SMILES of the each compounds obtained from“https://www.ebi.ac.uk/chembl/”

ADME properties of the studied compound were calculated using online SwissADME
(http://swissadme.ch) program. The major parameters for ADME associated properties such as Lipinski’s
rule of five, the solubility of the drug, pharmacokinetic properties and drug likeliness were considered.

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Lipinski Rule of five

Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of
thumb to evaluate druglikeness or determine if a chemical compound with a
certain pharmacological or biological activity has chemical properties and physical properties that would
make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in
1997, based on the observation that most orally administered drugs are relatively small and
moderately lipophilic molecules.

Objective

Lipinski rule of 5 helps in distinguishing between drug like and non drug like molecules. It predicts high
probability of success or failure due to drug likeness for molecules complying with 2 or more of the
following rules

 Molecular mass less than 500 Dalton

 High lipophilicity (expressed as LogP less than 5)

 Less than 5 hydrogen bond donors

 Less than 10 hydrogen bond acceptors

 Molar refractivity should be between 40-130

Limitation

The rule does not predict if a compound is pharmacologically active .

The rule is important to keep in mind during drug discovery when a pharmacologically active lea
structure is optimized step-wise to increase the activity and selectivity of the compound as well as to
ensure drug-like physicochemical properties are maintained as described by Lipinski's rule3 Candidate
drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an
increased chance of reaching the market.

In this work , I have taken the drugs which shows 0 violation in Lipinski’s rule.

After applying Lipinski’s rule , further I applied following rules that also for drug likeness properties-

- Ghose Filter
- Veber Filter
- Egan Filter
- Muegge Filter

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Ghose Filter

The Ghose filter is a drug-like filter described in Ghose, AK.; Viswanadhan, VN.; Wendoloski JJ.: A
knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug
discovery. A qualitative and quantitative characterization of known drug databases.,

 Molecular weight between 160 and 480

 LogP between -0.4 and +5.6
 Atom count between 20 and 70
 Molar refractivity between 40 and 130.

Veber Filter

The Veber filter is a rule of thumb filter for orally active drugs described in Veber et. al., J Med Chem.
2002; 45(12): 2615-23.

The default parameters used here are:

 Rotatable bonds <= 10

 Topological polar surface area(TPSA) <= 140

Egan Filter

Druglikeness Egan (Pharmacia) filter provides a prediction of drug absorption based on physical
processes involved in membrane permeability of a small molecule. Importantly, the Egan computational
model for human passive intestinal absorption (HIA) of small molecule accounts for active transport and
efflux mechanisms and is therefore robust in predicting the absorption of drugs.

TPSA > 131.6Å or log P > 5.88

*TPSA – Total Polar Surface Area

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Muegge(Bayers) Filter

Muegge’s filter includes 200 ≤ molecular weight ≤ 600,

−2 ≤ XLOGP3 (lipophilicity) ≤ 5,

The total polar surface area ≤ 150,

The number of rings ≤ 7,

The number of carbon > 4,

The number of heteroatoms > 1,

The number of rotatable bonds ≤15,

The hydrogen bond acceptors ≤ 10,

The hydrogen bond donors ≤ 5

After evaluating all the above mentioned drug-likeness properties, There was only 52 drugs out of 125,
which has passed the drug-likeness evaluation.

After evaluating drug-likeness properties, I have classified them according to their drug score.

On the basis of canonical SMILES of the each compounds , I have monitored the drug score as well as
monitored some of the toxicity risks like Mutagenicity ,Tumorigenicity , Irritating effects and
reproductive effects of each drug by using Osiris Property Explorer Web tool. In this study I have
monitored drug score of remaining 52 drugs.

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Drug Score

The drug score combines drug likeness, cLogP(partition coefficient), logs(solublity), molecular weight
and toxicity risks in one handy value than may be used to judge the compound's overall potential to
qualify for a drug. This value is calculated by multiplying contributions of the individual properties with
the first equation:

ds is the drug score. si are the contributions calculated directly from of cLogP, logS, molweight and
druglikeness (pi) via the second equation which describes a spline curve. Parameters a and b are (1, -5),
(1, 5), (0.012, -6) and (1, 0) for cLogP, logS, molweight and druglikeness, respectively. ti are the
contributions taken from the 4 toxicity risk types. The ti values are 1.0, 0.8 and 0.6 for no risk, medium
risk and high risk, respectively.

Mutagenicity

Mutagenicity refers to the induction of permanent transmissible changes in the amount or structure of
the genetic material of cells or organisms. These changes may involve a single gene or gene segment, a
block of genes or chromosomes. The genetic change is referred to as a mutation and the agent causing
the change as a mutagen.

No Observed Adverse Effect Level (NOAEL) cannot be obtained from mutagenicity/genotoxicity studies
due to study design and different mode of action. It is generally assumed that even a small dose of
mutagenic (genotoxic) chemicals may have a potential adverse effect. In general, the advice given by risk
assessors in Europe has been to keep exposure to such compounds at the lowest possible level - ALARA
principle (“as low as reasonably achievable”).

All known germ cell mutagens are also mutagenic in somatic cells in vivo. Substances that are mutagenic
in somatic cells may produce heritable effects if they, or their active metabolites, have the capability of

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interacting with the genetic material of germ cells. Substances that do not induce mutations in somatic
cells in vivo would not be expected to be germ cell mutagens.

There is considerable evidence of a positive correlation between the mutagenicity of substances in vivo
and their carcinogenicity in long-term studies with animals.

Tumorigenicity

Tumorigenicity is the tendency for cultured cells to give rise to either benign or malignant growing
tumors when infected to in immunologically nonresponsive animals. Assessing and managing the
tumorigenicity of all final products is essential in order to prevent ectopic tissue formation, tumor
development or malignant transformation elicited by residual pluripotent stem cells after implantation.

Irritating effects

An irritant toxic chemical causes reversible damage to skin or other organ system, whereas a corrosive
agent produces irreversible damage, namely, visible necrosis into integumentary layers, following
application of a substance for up to 4 hours. Corrosive reactions can cause coagulation or liquefaction
necrosis. Damaged areas are typified by ulcers, bleeding, bloody scabs, and eventual discoloration caused
by blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to
evaluate questionable lesions.

Reproductive effects

Reproductive toxicity is a hazard associated with some chemical substances, which interfere in some way
with normal reproduction; such substances are called reprotoxic. They may adversely affect sexual
function and fertility in adult males and females, as well as causing developmental toxicity in the
offspring. Reproductive toxicity is usually defined practically, to include several different effects which
are unrelated to each other except in their outcome of lowered effective fertility. The Globally
Harmonized System of Classification and Labelling of Chemicals (GHS) separates reproductive toxicity
from germ cell mutagenicity and carcinogenicity, even though both these hazards may also affect fertility.

Many drugs can affect the human reproductive system. Their effects can be

 desired (hormonal contraception),

 a minor unwanted side effect (many antidepressants) or
 a major public health problem (thalidomide)

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Hence compounds having –

- No risk of Mutagenicity

- No risk of Tumorigenicity

-No Irritating effect

- No Reproductive effect

Also having good drug score value is considered to be safe and hence after evaluating from all these
parameters , I got total 12 drugs which has passed all the toxicity risk and have good drug score.

After evaluating from all these toxicity risk and classifying according to Drug score , I have applied Pan-
assay interference compounds (PAINS) filter.

PAINS (Pan-assay interference compounds)

Pan-assay interference compounds (PAINS) are chemical compounds that often give false positive results
in high-throughput screens. PAINS tend to react nonspecifically with numerous biological targets rather
than specifically affecting one desired target. A number of disruptive functional groups are shared by
PAINS is likely to interfere in screening technologies via a number of means but particularly through
protein reactivity. They represent poor choices for drug development and yet can furnish data that in
isolation may be suggestive of a selective and optimizable hit.

Hence compounds showing 0 violations in PAINS filter and after evaluating them from all the above
mentioned parameters, I got total 9 compounds.

So, in my study I have identified 9 potential inhibitors, they are:-

1)Captopril

2)Onalespib

3)Pioglitazone

4) imidazoisoquinoline SDZ-62-434

5)Tyrphostin AG 1296

6)Alvocidib Hydrochloride

7) TDZD-8 (thiadiazolidine derivative that acts as a non-ATP competitive inhibitor of the GSK-3β)

8)Anisomycin

9) PF-04691502 (potent and selective inhibitor of PI3K and mTOR)

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The Parameters which I have studied in this work can be summarized as –

Collection of data
• From ChemBL

Drug Likeness Property

• Lipinski's rule of 5
• Ghose Filter
• Veber
• Egan Filter
• Muegge (Bayers filter)

Drug Score
• Toxicity Properties

And at last applied PAINS filter

And then I got final list of 9 drugs, which according to this study will be inhibitor of SARS-CoV-2.

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Table:-ADME Properties of obtained COVID-19 major inhibitors

ADME Properties (Lipinki’s Rule of Five)
Compound
Properties Value

Captopril Molecular weight (<500Da)

C9H15NO3S 217.2853
LogP (<5)
0.5658
H-Bond donor (5)
2
H-bond acceptor (<10)
7

Violations 0
ONALESPIB Molecular weight
C24H31N3O3
409.52124
(<500Da)

LogP (<5) 2.9383

H-Bond donor (5) 2
H-bond acceptor (<10) 6
Violations 0

PIOGLITAZONE Molecular weight

(<500Da) 356.4387
C19H20N2O3S
LogP (<5) 3.48
H-Bond donor (5) 1.0
H-bond acceptor (<10) 6.0
Violations 0

SDZ-62-434 Molecular weight

C23H25N3 409.52124
(<500Da)
LogP (<5)
2.93
H-Bond donor (5
2.0

H-bond acceptor (<10) 6.0

Violations 0

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TYRPHOSTIN AG 1296
C16H14N2O2
266.29456
Molecular weight

(<500Da)

LogP (<5) 3.31

H-Bond donor (5) 0

H-bond acceptor (<10) 4

0
Violations

ALVOCIDIB Molecular weight

HYDROCHLORIDE 438.30114
C21H21Cl2NO5
(<500Da)

LogP (<5) 4.04

H-Bond donor (5) 4.0

H-bond acceptor (<10) 7.0

Violations 0

TDZD-8 Molecular weight

222.26
C10H10N2O2S (<500Da)

LogP (<5) 0.65

H-Bond donor (5) 0.0

H-bond acceptor (<10) 2.0

Violations 0

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Anisomycin

C14H19NO4 Molecular weight (<500Da) 265.60

LogP (<5) 0.83

H-Bond donor (5) 2.0

H-bond acceptor (<10) 8.0

Violations 0

PF-04691502

C22H27N5O4 Molecular weight (<500Da) 425.48

LogP (<5) 2.82

H-Bond donor (5) 2.0

H-bond acceptor (<10) 10.0

Violations 0

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CONCLUSION

The drug repurposing approach would be the fast and most approapriate option to find therapeutic
solutions for the SARSCoV2, the Novel Coronavirus (COVID-19). The bioinformatics approach could be
a very useful tool to identify potent inhibitors against the Novel Coronavirus. In this study, we have used
Bioinformatics tools, SwissADME and Osiris Property Explorer to identify potent FDA approved
inhibitors against COVID-19 collected from ChEMBL, which play crucial role in Coronavirus
propagation. We have identified 9 potent inhibitors from the library of thousands of compounds and
found Captopril, Onalespib, Pioglitazone, SDZ-62-434, Tyrphostin AG 1296, Alvocidib Hydrochloride,
TDZD-8, Anisomycin, PF-04691502 as appropriate inhibitors against COVID-19 Main Proteases.

This findings suggest that these small molecules can be used as potential inhibitors against SARS‐CoV-2.
However, further investigation and validation of these inhibitors against SARS‐CoV‐2 are needed to
claim their candidacy for clinical trials.

Further they can also be used in molecular docking method,as it is one of the most frequently used
methods in structure-based drug design, due to its ability to predict the binding-conformation of small
molecule ligands to the appropriate target binding site.

They can also be used for bioassay, which is an analytical method to determine concentration or potency
of a substance by its effect on living cells or tissues. Bioassays are quantitative biological assays used to
estimate the potency of agents by observing their effects on living animals (in vivo) or tissue/cell culture
systems.

Owing to the significance in the above context, such preliminary screening of molecules is the need of the
hour in order to discover and develop novel therapeutic agents with improved efficacy.

Since these drugs have been used in the treatment of different ailments, the medicinal roles of these plants
could be used to treat SARS-CoV-2.

The quantitative analysis of these molecules will be an interesting area for further study. Efforts should be
geared up to exploit the biomedical applications of these screened molecules.

Hence, the above mentioned drugs could be explored for its highest therapeutic efficacy by
pharmaceutical companies in order to develop safe drugs for various ailments.

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2) Comprehensive Toxicology , IIIrd edition by Charlene A. McQueen , University of Arizona, Tucson,

AZ, United States, Elsevier Science Publication,2018.

3) Dyall, J.; Coleman, C.; Hart, B.; Venkataraman, T.; Holbrook, M.R.; Kindrachuk, J.; Johnson, R.F.;
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7) https://www.ebi.ac.uk/chembl/

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16) https://www.creative-biolabs.com/drug-discovery/therapeutics/

17) https://en.wikipedia.org/

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