ijlpr 2020; doi 10.22376/ijpbs/lpr.2021.11.1.

L107-122

International Journal of Lifescience and Pharma Research

Zoology
Research Article

In Silico Identification of Clinically Approved Medicines Against the main

Protease of Sars-Cov-2 – A Causative Agent of Covid-19
Estari Mamidala1*, Rakesh Davella2, Swapna Gurrapu3 and Pujala Shivakrishna4
1-4
Infectious Diseases Research Lab, Department of Zoology, Kakatiya University, Warangal-506009, Telangana, Indiau, India.

Abstract: The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive
drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA.
There is presently no exact drug or treatment for this disease caused by SARS-CoV-2.Speeding up drug innovation is
immediately required. In the present study, we report the potential inhibitory activity of some FDA approved drugs against
SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active sites. Total 47 FDA
approved drugs were selected for molecular docking with main COVID-19 protease. The docking of selected drugs to the active
site of protein was performed using AutoDock software. Docking was achieved to attain a population of potential conformations
and alignments for the ligand at the binding site. Docking study revealed that great inhibitory efficacy of the one anti-H1N1 drug
(Oseltamivir), one anti-TB drug (Rifampin), four anti-HIV drugs (Maraviroc, Etravirine, Indinavir, Rilpivirine) and seven anti-
malarial drugs (Atovaquone, Quinidine, Halofantrine, Amodiaquine, Tetracylcine, Azithromycin, hydroxycholoroquine) was found
since they could launch H2 bonds with different amino acid residues that caused an inhibition of SARS-CoV-2 protease activity
with higher binding affinity ranging from (-10.67 to -8.3 kcal/mol). However, the in-silico abilities of the drug molecules tested in
this study, further needs to be validated by carrying out in vitro and in vivo studies. Moreover, this study spreads the potential use
of current drugs to be considered and used to comprise the fast expanding SARS-CoV-2 infection.

Keywords: COVID-19, SARS-CoV-2 main protease, Molecular docking, FDA, Coronavirus

*Corresponding Author Recieved On 23 April 2020

Estari Mamidala , Infectious Diseases Research Lab, Revised On 12 June 2020

Department of Zoology, Kakatiya University, Warangal- Accepted On 29 June 2020
506009, Telangana, Indiau, India. Published On 07 January 2021

Funding This research did not receive any specific grant from any funding agencies in the public, commercial or not for profit sectors.

Citation Estari Mamidala*, Rakesh Davella , Swapna Gurrapu and Pujala Shivakrishna , In Silico Identification of Clinically Approved
Medicines Against the main Protease of Sars-Cov-2 – A Causative Agent of Covid-19.(2021).Int. J. Life Sci. Pharma Res.11(1), L107-
122 http://dx.doi.org/10.22376/ijpbs/lpr.2021.11.1.L107-122

This article is under the CC BY- NC-ND Licence (https://creativecommons.org/licenses/by-nc-nd/4.0)

Copyright @ International Journal of Life Science and Pharma Research, available at www.ijlpr.com

Int J Life Sci Pharma Res., Volume11., No 1 (Jan) 2021, pp L107-122

ijlpr 2020; doi 10.22376/ijpbs/lpr.2021.11.1.L107-122 Zoology

1. INTRODUCTION most patients.10This encouraged us to accomplish a

systematic study on some clinically approved medicines using
A new occurred human coronavirus (COVID-19) is informed molecular docking and reinvestigate their biological efficacies
in December 2019 in Wuhan, China.1,2 Afterward, the and pharmacological properties. However, there is no
COVID-19 underway spreading across the world, making the organized study on the inhibition of the coronavirus by
whole world on high attentive.3 The World Health clinically approved drugs to the best of our knowledge.
Organization (WHO) surveillance draft in January 2020 stated Hence, the present study was aimed at molecular docking
that, any traveller to Wuhan, Hubei Province in China, two studies of clinically approved drugs against the main protease
weeks earlier the onset of the signs, is supposed to be a of SARS-CoV-2.
COVID-19 case.4,5 On April 21st, 2020, a total of 2,31,4621
confirmed infections were reported worldwide, with 1,57,847 2. MATERIALS AND METHODS
deaths with a increasing mortality rate of >4.3%.5 The World
Health Organization (WHO) strategy to comprise the 2.1 Molecular Docking Methods
distribution includes the decrease of human-to-human
dispersal by preventing the interaction between individuals, For molecular docking, Auto-Dock 4.2.6 software was
accordingly avoiding transmission extension events and used.11The free energy (DG) binding of SARS-CoV-2 viral
interactive critical risk evidence to all populations.5 In India, protease with the selected FDA approved drugs was created
the first case of the COVID-19 was reported in Kerala on 30 by means of this molecular docking package. Docking is a
January 2020. As of 21 April, 2020, there are 14,255 cases computational simulation method of a ligand binding to a
and 559 deaths as reported by the Ministry of Health and receptor or enzyme and expects the favored orientation of
Family Welfare, Government of India.6 COVID-19 is a binding of one molecule to the second to form a steady
member of Beta coronaviruses similar to the Severe Acute complex. To predict the attraction and activity of binding of
Respiratory Syndrome Human coronavirus (SARS HCoV) and the minor molecule to their enzyme targets by using scoring
the also the Middle-East Respiratory Syndrome Human functions docking is used. Therefore, docking shows
coronavirus (MERS HCoV).7 Main protease (Mpro) is one of significant role in the rational design of medicines. The
the greatest-characterized drug targets among sensitivity of docking calculations concerning the geometry of
coronaviruses.8 Beside with the papain-like protease(s), this the involvement ligand displays that even minor changes in
main protease enzyme is vital for processing the polyproteins the ligand structure can lead to big changes in the geometries
that are translated from the viral RNA.8 This crucial function and scores of the subsequent docked poses.
of main protease in virus replication makes this enzyme a
capable target for the expansion of inhibitors and possible 2.2 Selection of Ligand
treatment remedy for infection of novel coronavirus. To date,
no precise therapeutic medicine or vaccine has been accepted Antiviral and anti-malarial medications were recognized as
for the management of human coronavirus due to natural potential coronavirus inhibitors from diverse literature
evolution of receptor-binding domain (RBD) portion of the evaluations. Total 47 FDA approved drugs were selected for
SARS-CoV-2 spike proteins. Some clinical trials, it has been molecular docking with main COVID-19 protease. Among
described that anti-HIV drugs and chloroquine phosphate, an the 47 approved drugs, 2 drugs are anti-H1N1 drugs, 4 are
anti-malarial drug, has a assured therapeutic effect on the anti-TB drugs, 24 are anti-HIV-1 drugs and 17 are anti-
COVID-19.9 In specific, chloroquine phosphate is suggested malarial drugs selected from the PubChem database
to treat COVID-19 related pneumonia in larger inhabitants in (https://pubchem.ncbi.nlm.nih.gov/). The SDF format three-
the future. Subsequently, other clinical trials suggested that dimensional structure files of the selected FDA approved
hydroxychloroquine supplementary with azithromycin is very drugs were downloaded from the PubChem database and
effective in clearing viral naso-pharyngeal carriage of SARS- were used for molecular docking. Molecular 2D structures of
CoV-2 in COVID-19 patients in only three to six days, in selected FDA approved drugs are shown inFig.1.

Oseltamivir (anti-H1N1) Zanamivir (anti-H1N1) Isoniazid (anti-TB)

Rifampin (anti-TB) Ethambutol (anti-TB) Pyrazinamide (anti-TB)

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Abacavir (anti-HIV) Atazanavir (anti-HIV) Darunavir (anti-HIV)

Delavirdine (anti-HIV) Dolutegravir (anti-HIV) Doravirine (anti-HIV)

Efavirenz (anti-HIV) Elvitegravir (anti-HIV) Emtricitabine (anti-HIV)

Etravirine (anti-HIV) Fosamprenavir (anti-HIV) Indinavir (anti-HIV)

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Lamivudine (anti-HIV) Lopinavir (anti-HIV) Maraviroc (anti-HIV)

Nevirapine (anti-HIV) Raltegravir (anti-HIV) Rilpivirine (anti-HIV)

Ritonavir (anti-HIV) Saquinavir (anti-HIV) Stavudine (anti-HIV)

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Tenofovir (anti-HIV) Tipranavir (anti-HIV) Zidovudine (anti-HIV)

Quinine (anti-malarial) Quinidine (anti-malarial) Mefloquine (anti-malarial)

Chloroquine (anti-malarial) Amodiaquine (anti-malarial) Primaquine (anti-malarial)

Halofantrine (anti-malarial) Sulfadoxine (anti-malarial) Sulfamethoxypyridazine

(anti-malarial)

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Proguanil (anti-malarial) Pyrimethamine (anti-malarial) Tetracycline (anti-malarial)

Doxycycline (anti-malarial) Clindamycin (anti-malarial) Azithromycin (anti-malarial)

Artemisinin (anti-malarial) Atovaquone (anti-malarial) Hydroxychloroquine

(anti-malarial)

Fig 1. Structures of clinically approved drugs

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2.3 Selection of Target key residues of amino acids within the binding pocket of viral
protease and may too have a higher tolerance to conflict
The main COVID-19 protease remained used as a target to mutations. The crystal 3D structure of SARS-CoV-2 protease
novelty repurposing candidates over computational selection (PDB ID:6LU7) with hydrophobic loop remained obtained
amongst clinically accepted drugs. The study identified a list of from Protein-Data Bank and showed in fig.2.12
FDA permitted 47 drugs that may form hydrogen bonds to

Fig 2.The 3D crystal structure of SARS-CoV-2 protease (PDB ID: 6LU7)

Meanwhile this protease has its crystal structure in a state binding site and its energy and inhibition constant. The energy
that signifies the pharmacological target for the progress of of interaction of every atom in the ligand was met. For each
new medicines to treat diverse infectious diseases. The ligand, 10 best postures were made and scored using Auto-
preparation of the target enzyme 6LU7 with the Auto-Dock Dock 4.2 scoring purposes.14
Tools software intricate addition of all H2 atoms to the
enzyme, which is a step essential for accurate calculation of 3. RESULTS
fractional atomic charges. The ligand and all water molecules
were detached to make the structure for docking. Gasteiger Computational approaches for drug discovery and
charges are considered for each atom of the protein in development are proven to be effective and time efficient, as
AutoDock 4.2 instead of Kollman charges, which were used they are not based on difficult laborious works. The protein-
in the earlier versions of this package. ligand docking elucidates the mechanism of inhibition along
with the specificity and efficiency of that ligand as an inhibitor.
2.4 Docking Procedure The association of drug candidate (ligand) to its target
receptor is a fundamental binding reaction and the aim of the
For ligand conformational incisive, we take the ‘Lamarckian- computer-aided drug discovery is to find small molecules
genetic algorithm (LGA)’, which is a mixture of a genetic having strong inhibitory or activating action against the
algorithm and a native search algorithm. This algorithm biological targets. The strength of inhibition or activation is
initially builds a population of entities, being a diverse casual elucidated through binding affinity.15
conformation of the docked enzyme. Each distinct protein is
then mutated to attain a slightly diverse translation and 3.1 Docking Prediction of anti-H1N1 drugs
alternation and the local search algorithm then achieves
energy minimizations on a user-specified amount of the Oseltamivir and Zanamivir, two FDA approved drugs docked
population of individuals. The entities with the low with SARS-CoV-2 main protease and obtained binding energy,
subsequent energy are moved to the succeeding generation are −7.39 kcal/mol and -3.88 kcal/mol respectively (Table 1).
and the procedure is then repetitive. This algorithm is called Oseltamivir interacted with Glu:166, Pro:52, 168, Met:49,165,
Lamarckian while every novel group of entities is allowed to Leu:167, His:164, 41, Tyr:54, Gln:189, Arg:188, Asp:187,
receive the local search variations of their parents.To get Thr:190 and Gln:192 at the binding site of this SARS-CoV-2
many docked structures, Auto-Dock was run numerous protease and Zanamivir interacted with Glu:166, Leu:167,
times, and used to examine the expected docking energy. Met:165, Gln:189, 192, Thr:190, Ala:191, Pro:168, Gly:170 at
Rapid energy assessment was attained by pre-calculating the binding site of this protease (fig.3). The results identified
nuclear affinity capacities for every atom in the compound that Oseltamivir is a potential inhibitor of the SARS-CoV-2
molecule. The binding sites of the target enzyme for these main protease. Earlier one study has reported that
molecules in the AutoGrid process were designated on the Oseltamivir is a prodrug of oseltamivir carboxylate, a potent
patterns of founded ligand-binding pockets.13 Auto-Dock and selective inhibitor of the neuraminidase glycoprotein
Tools deliver various approaches to examine the outcomes essential for replication of influenza A and B viruses.16
of docking-simulations such as, structural resemblance, and
other limitations like intermolecular energy, visualizing the

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Table 1. Molecular docking analysis of anti-H1N1 drugs against COVID-19 Protease (6LU7)
Binding Interaction of
Compound No. of H
Sl. No energy Residue involving interaction residues forming H2
Name bonds
(kcal/mol) bonds
GLU:166, PRO:52, 168, MET:49,165, LEU:167,
1 Oseltamivir -7.39 HIS:164, 41, TYR:54, GLN:189, ARG:188, 1 GLU:166
ASP:187, THR:190, GLN:192
GLU:166, LEU:167, MET:165, GLN:189, 192,
2 Zanamivir -3.88 4 GLU:166, LEU:167
THR:190, ALA:191, PRO:168, GLY:170

Fig 3.Docking visualisation of COVID-19 protease (6LU7) with Oseltamivir (anti-H1N1 drug)

3.2 Docking Prediction of anti-TB drugs 9.41 kcal/mol among all the four drugs. The residues involved
in the interaction with the Rifampin were Glu:166, Met:165,
Isoniazid, Rifampin, Ethambutol and Pyrazinamide are clinically His:163, 172, 164, 163, Phe:140, Leu:141, 167, Ser:144,
approved drugs were docked with binding energy -4.83, -9.41, Gly:143, Asn;142, Pro:163, Gln:192, Cys:145, Ala:191,
-5.02 and -4.05 kcal/mol respectively against SARS-CoV-2 Thr:190 and Gln:189 (fig.4).
protease (Table 2). Rifampin showing highest binding affinity -

Table2.Molecular docking analysis of anti-TB drugs against COVID-19 Protease (6LU7)

Binding No. of Interaction of
Sl. Compound
energy Residue involving interaction H residues forming
N Name
(kcal/mol) bonds H2 bonds
MET:49, 165, ASP:187, TYR:54, GLN:189, MET:49, TYR:54,
1 Isoniazid -4.83 4
HIS:41, PRO:52, ARG:188 ASP:187
GLU:166, MET:165, HIS:163, 172, 164, 163,
PHE:140, LEU:141, 167, SER:144, GLY:143,
2 Rifampin -9.41 1 GLU:166
ASN;142, PRO:163, GLN:192, CYS:145,
ALA:191, THR:190, GLN:189
LEU:141, ASN;142, GLU:166, HIS:163,172,
LEU:141, ASN:142,
3 Ethambutol -5.02 MET:165, SER:144, GLY:143, CYS:145, PHE:140, 4
GLU:166
GLY:170
VAL:303, 212, THR:304, 257, GLN:256, VAL:303, THR:304,
4 Pyrazinamide -4.05 3
GLN:306, ARG:217, ILE:213 GLN:256

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Fig 4. Docking visualisation of COVID-19 protease (6LU7) with anti-TB drug Rifampin

3.3 Docking Prediction of anti-HIV drugs Leu:177,87, Cys:38, Tyr:37, Glu:178, Asn:84, Arg:40, Indinavir
interacted at Glu:166, Gln:189, 192, Cys:145, Met:49, 165,
Twenty-four FDA approved anti-HIV drugs were docked with Asp:187, His:41, 164, 163, Asn:142, Leu:167, 141, Pro:168,
SARS-CoV-2 protease. Among the twenty four drugs, four Thr:190, Phe:140, Ser:144, 46, Arg:188 and Rilpivirine
drugs Maraviroc, Etravirine, Indinavir and Rilpivirine were interacted at Glu:166, Cys:44, 145, His:164, 41, Met:165, 49,
showed more potential inhibitors of SARS-CoV-2 main Ala:191, Pro:168,52, Gln:189, Tyr:54, Asp:187, Arg:188,
protease with binding affinity -10.67, -10.33, -10.00 and -9.66 Leu:167, Thr:190 of the SARS-CoV-2 main protease (fig.5). A
kcal/mol respectively (Table3). Maraviroc interacted at joint research team of the Shanghai Institute of
His:164, 41, Tyr:54, Asp:187, Met:165, 49, Leu:167,141, MateriaMedica and Shanghai Tech University performed drug
Pro:168, Cys:44, 145, Arg:188, Gly:143, Asn:142, Ala:191, screening in silicon and an enzyme activity test, and
Gln:192, 189, Thr:190, Etravirine interacted at Gln:83, Lys:88, they reported 30 anti-HIV agents with potential antiviral
Thr:175, Met:82, 162, His:164, Cys:85,38, Gly:179, Pro:39, activity against SARS-CoV-2 on January 25, 2020.17

Table3. Molecular docking analysis of anti-HIV drugs against COVID-19 Protease (6LU7)
Binding No. of Interaction of
Sl. Compound
energy Residue involving interaction H residues forming
N Name
(kcal/mol) bonds H2 bonds
MET:49, 165, GLN:189,192, HIS:41, THR:190,
1 Abacavir -7.77 ASP:189, TYR:54, PRO:52,168 LEU:50,167, 1 MET:49
ARG:188, GLU:166,
LYS:137,5, GLU:288,290, TYR:126, LEU:287,286,
2 Atazanavir -5.08 ASP:289, VAL:125, PHE:3, 291, ARG:4, CYS:128, 1 LYS:137
GLY:138, GLN:127, ALA:7,
GLN:189,192, GLU:166, PHE:140, PRO:168,
MET:165, LEU:167, THR:190, GLN:192, GLY:143, GLN:189, GLU:166,
3 Darunavir -6.08 3
CYS:145, SER:144, HIS:163,164, 172, LEU:141, PHE:140
ASN:142,
TYR:54, GLU:166, ALA:191, MET:165,49, LEU:167,
4 Delavirdine -7.89 50, GLN:192, 189, PRO:168, HIS:41,164, 2 TYR:54, GLU:166
ARG:188, ASP:187, THR:190,
GLU:166, MET:165, 49, GLN:192, THR:190,
PRO:168, LEU:167, 27 ALA:191, ARG:188,
5 Dolutegravir -7.75 1 GLU:166
GLN:189, HIS:164, 41, CYS:145, GLY:143,
ASN:142, SER:144
THR:190, 25,ARG:188, TYR:54, MET:165, 49,
THR:190, TYR:54,
6 Doravirine -8.15 ASP:187, HIS:41, GLN:189, 192, GLU:166, 3
ARG:188
HIS:164, GLY:143, LEU:27, THR:25,
GLY:143, CYS:145, ASN:142, MET:49, HIS:41,163,
7 Efavirenz -6.61 164, THR:26, LEU:27, 141, SER:144, PHE:140, 1 GLY:143
GLU:166, MET:165, GLN:189
THR:190,ASN:142, CYS:145, MET:165, 49,
GLN:192, 189, PRO:168, ARG:188, GLU:166,
8 Elvitegravir -7.98 1 THR:190
LEU:167, 141, GLY:143, SER:144, HIS:163, 164,
PHE:140, ASP:187,
HIS:41, 164, GLU:166, MET:165,49, THR:190,
9 Emtricitabine -4.79 2 HIS:41, GLU:166
ARG:188, GLN:192, 189, TYR:54, ASP:187,
GLN:83, LYS:88, THR:175, MET:82, 162, HIS:164,
10 Etravirine -10.33 2 GLN:83
CYS:85,38, GLY:179, PRO:39, LEU:177,87,

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CYS:38, TYR:37, GLU:178, ASN:84, ARG:40

ASN:203, 151, PRO:293, PHE:8,294, ILE:249, 200,
11 Fosamprenavir -4.08 106, VAL:202, 104, GLN:110, THR:292, GLY:109, 1 ASN:203
ASP:153, VAL:104, SER:158,
GLU:166, GLN:189, 192, CYS:145, MET:49, 165,
ASP:187, HIS:41, 164, 163, ASN:142, LEU:167,
12 Indinavir -10.00 3 GLU:166, GLN:189
141, PRO:168, THR:190, PHE:140, SER:144, 46,
ARG:188
PHE:140, GLU:166, SER:144, CYS:145, HIS:164, PHE:140, GLU:166,
13 lamivudine -4.75 41, 163, 172, MET:49, 165, ASN:142,LEU:141, 5 SER:144, CYS:145,
GLY:143 HIS:164

GLU:166, ASN:142, SER:144, HIS:163,164

14 Lopinavir -6.11 PHE:140, CYS:145, LEU:141,167 ARG:188, 1 GLU:166
MET:165, GLN:189,192, ALA:191, THR:190

HIS:164, 41, TYR:54, ASP:187, MET:165, 49,

LEU:167,141, PRO:168, CYS:44, 145, ARG:188,
15 Maraviroc -10.67 2 TYR:54, HIS:164,
GLY:143, ASN:142, ALA:191, GLN:192, 189,
THR:190,
MET:49, 165, HIS:41, 164, SER:144, CYS:145,
16 Nevirapine -6.44 0 0
GLU:166, GLN:189, ASP:187, ARG:188, TYR:54
SER:144, CYS:145, GLU:166, PRO:168,MET:49,
SER:144, CYS:145,
17 Raltegravir -7.81 165, HIS:41,163,172, 164, LEU:141, 167, PHE:140, 3
GLU:166
GLY:143, ASN:142, GLN:189, THR:190, ARG:188,
GLU:166, CYS:44, 145, HIS:164, 41, MET:165, 49,
HIS:164, CYS:44,
18 Rilpivirine -9.66 ALA:191, PRO:168,52, GLN:189, TYR:54, 3
GLU:166
ASP:187, ARG:188, LEU:167, THR:190,
GLY:143,170, GLU:166, LEU:141,27,167, PHE:140,
CYS:145, ASN:142, HIS:41, ASP:187, MET:49,163
19 Ritonavir -8.25 1 GLY:143
ARG: 188, GLN:189,192, THR:190, ALA:191,
GLY:170, PRO:168,
GLY:302, 2, ARG:298, SER:301,1, PRO:9,
ARG:298, GLY:302,
20 Saquinavir -7.55 VAL:297,303, MET:6, CYS:300, ALA:7, PHE:8, 5
SER:301
GLY:2
ARG:188, GLN:189, 192, HIS:41, 164, MET:165,
21 Stavudine -5.38 THR:190, GLN:192, VAL:186, TYR:54, ASP:187, 2 ARG:188
GLU:166
THR:190, GLU:166, MET:165, 49, ALA:191,
22 Tenofovir -4.40 GLN:189, 192, ARG:188, ASP:187, PRO:168, 2 THR:190, GLU:166
LEU:167, HIS:41
GLN:189, GLU:166, ASN:142, MET:49, CYS:145,
MET:165, 49, HIS:41, 164, 163, SER:144, 46, GLN:189, ASNl142,
23 Tipranavir -8.30 3
PHE:140, LEU:141, ARG:188, ASP:187, TYR:54, GLU:166
GLY:143,
ASP:187, GLU:166, ARG:188, TYR:54,
24 Zidovudine -6.31 MET:165,49, GLN:189, HIS:164,41, PHE:181, 2 ASP:187, GLU:166
PRO:52CYS:44

(A) Maraviroc

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(B) Etravirine

(C) Indinavir

(D) Rilpivirine

Fig 5. Docking visualisation of COVID-19 protease (6LU7) with anti-HIV drugs, Maraviroc (A), Etravirine (B),
Indinavir (C) and Rilpivirine (D).

3.4 Docking Prediction of antimalarial drugs was shown in fig.6. Among the seven potent inhibitors
Atovaquone was more potent with binding affinity -8.95
Seventeen clinically approved antimalarial drugs were docked kcal/mol. Asn:142, Glu:166, Leu:141, Met:49, 165, Cys:44,
with SARS-CoV-2 protease. Out of seventeen, seven drugs Pro:52, Tyr:54, Arg:188, Asp:187, His:41,164, 163, 172,
were shown more potential inhibitors of SARS-CoV-2 main Phe:140 and Gln:189 are the amino acid residues involved in
protease. Atovaquone, Quinidine, Halofantrine, Amodiaquine, the interaction with Atovaquone (fig.6). As these residues
Tetracycline, Azithromycin and hydroxychloroquine docked play an important role during protein-ligand interaction, they
with binding affinity -8.95, -8.84, -8.68, -8.65, -8.4, -8.32 and - may serve as a biomarker during the drug discovery
8.30 kcal/mol against SARS-CoV-2 main protease (Table4). process.18
Docking visualization of 6LU7 with seven antimalarial drugs

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Table4. Molecular docking analysis of anti-malarial drugs against COVID-19 Protease (6LU7)
Binding No. of Interaction of
Sl.
Compound Name energy Residue involving interaction H residues forming
N
(kcal/mol) bonds H2 bonds
GLN:189, HIS:172,41, 164, 163 CYS:145,
MET:165, 49, GLU:166, ARG:188, TYR:54,
1 Quinine -7.86 1 GLN:189
ASN:142, PHE:140, SER:144, LEU:141,
GLY:143, ASP:187
GLN:189, MET:165, 49, TYR:54, PRO:52,
HIS:41, 164, PHE:181, ASP:187, GLU:166,
2 Quinidine -8.84 1 GLN:189
ASN:142, CYS:145, SER:144, GLY:143, THR:26,
25, LEU:27, VAL:186
GLN:189,192, TYR:54, GLU:166, ARG:188,
ASP:187, MET:49, LEU:167, 141, THR:190, GLN:189,192,
3 Mefloquine -7.47 3
MET:165, HIS:163, 172, 164,41, LEU:167, TYR:54
CYS:145, PHE:140, SER:144,
HIS:164,163, 41, 172, ARG:188, PRO:52,
TYR:54, MET:49, 165, ASP:187, GLN:189,
4 Chloroquine -7.62 1 HIS:164
GLU:166, LEU:141, SER:144, CYS:145,
ASN:142, PHE:140
LEU:141,SER:144, HIS:41, 172, 163, 164,
GLN:189, 192, MET:165,49,PHE:140, ASP:187,
5 Amodiaquine -8.65 2 LEU:141, SER:144
ARG:188, THR:190, GLN:192, GLU:166,
ASN:142, GLY:143, CYS:145,
GLU:166, LEU:167, GLY:170, ASP:187,
6 Primaquine -7.15 GLN:189, MET:165, ARG:188, GLN:192, 4 GLU:166, LEU:167
THR:190, PRO:168
GLN:192, 189, THR:190, ARG:188, GLU:166,
CYS:145, MET:49, 165, HIS:164, ASP:187,
7 Halofantrine -8.68 2 THR:190, GLN:192
TYR:54, PRO:168, LEU:167, 141,SER:144,
HIS:163, GLY:143,
HIS:164,41, 172, 163, SER:144, LEU:141,
CYS:145, MET:49, 165 GLU:166, PRO:52, SER:144, LEU:141,
8 Sulfadoxine -6.47 3
TYR:54, ARG:188, ASP:187, GLN:189, HIS:164
ASN:142
HIS:163,164, 41,172, SER:144,LEU:141,MET:49,
165, ASP:187,ASN:142, PHE:140, GLU:166, HIS:163,164,
9 Sulfamethoxypyridazine -7.40 4
GLN:189, TYR:54, PRO:52, CYS:145, ASN:142, SER:144, LEU:141
GLY:143,
HIS:163, 172 GLU:166, LEU:141, PHE:140,
10 Proguanil -7.81 MET:165, SER:144, GLY:143, ASN:142, 4 HIS:163
CYS:145
ASN:142, GLU:166, PHE:140, HIS:172, 163, 41,
ASN:142,
11 Pyrimethamine -6.85 LEU:141, SER:144, MET:165, CYS:145, MET:49, 3
GLU:166, PHE:140
GLY:143,
GLU:166, ASN:142, LEU:141, SER:144, GLU:166, LEU:141,
12 Tetracycline -8.40 CYS:145, MET:165,49, GLN:189, ASP:187, 6 SER:144, CYS:145,
ARG:188, PHE:140, HIS:41,163,172, GLY:143 ASN:142,
GLN:189, ASN:142, GLU:166, SER:144, GLN:189,
13 Doxycycline -8.30 MET:165, HIS:172, 163, PHE:140, LEU:141, 6 ASN:142,
CYS:145 GLU:166, SER:144
ILE:152, PHE:294, 8, ARG:198, PRO:9,
14 Azithromycin -8.32 1 ILE:152
VAL:297, SER:301, ASP:153, TYR:154, ASN:151
MET:165, 49, HIS:41, 164, ARG:188, GLU:166,
15 Artemisinin -7.63 0 0
GLN:189, CYS:145, 44, TYR:54, ASP:187,
ASN:142, GLU:166, LEU:141, MET:49, 165,
16 Atovaquone -8.95 CYS:44, PRO:52, TYR:54, ARG:188, ASP:187, 1 ASN:142
HIS:41,164, 163, 172, PHE:140, GLN:189
GLN:189, ARG:188, MET:165, TYR:54,
ASP:187, HIS:41,172,163,164, PHE:140,
17 Hydroxychloroquine -8.30 1 GLN:189
LEU:141, CYS:145, SER:144, ASN:142,
GLY:143, GLU:166

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(A) Atovaquone

(B) Quinidine

(C) Halofantrine

(D) Amodiaquine

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(E) Tetracycline

(F) Azithromycin

(G) Hydroxychloroquine

Fig 6. Docking visualisation of COVID-19 protease (6LU7) with anti-malarial drugs, Atovaquone (A), Quinidine
(B), Halofantrine (C), Amodiaquine (D), Tetracycline (E), Azithromycin (F) and hydroxychloroquine (G)

This study focused on identification of potential inhibitors protease. This study provides the support of the repurposed
against SARS-CoV-2 from corona virus to control the viral drugs, which may be helpful for the treatment of novel
replication. Outcomes from the In silico molecular docking coronavirus disease and can serve as potential drug
study maintained the great inhibitory efficacy of the one anti- candidates to curb the ongoing and ever enlarging COVID-19
H1N1 drug (Oseltamivir), one anti-TB drug (Rifampin), four pandemic. Since all the drugs used in this study are of known
anti-HIV drugs (Maraviroc, Etravirine, Indinavir, Rilpivirine) pharmacokinetics standards and approved by FDA for human
and seven antimalarial drugs (Atovaquone, Quinidine, use they do not need to undergo specific long term clinical
Halofantrine, Amodiaquine, Tetracycline, Azithromycin, trials and therefore can fasten up the process of therapeutics
hydroxychloroquine) since they could launch H2 bonds with development.
different amino acid residues that caused in an inhibition of
SARS-CoV-2 protease activity with higher binding affinity 4. DISCUSSION
ranging from (-10.67 to -8.3 kcal/mol). Thus, the projected
binding interactions of the dynamic molecules with the Coronavirus fits a set of viruses which can contaminate
protease by the docking study evidently established their vertebrate animals and humans. It has slaughtered thousands
inhibitory strength towards catalytic response of the of individuals around the world with growth in mortality rate

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each single day. Digestive, central nervous system, liver, Among the 17 anti-malarial approved drugs, Atovaquone
respiratory systems of humans and animals hampered by this presented best docking score (-8.95 kcal/mol) and ASN:142,
virus infection.19 Our study was focused on the FDA GLU:166, LEU:141, MET:49, 165, CYS:44, PRO:52, TYR:54,
approved drugs against the main protease in coronavirus, as a ARG:188, ASP:187, HIS:41,164, 163, 172, PHE:140, GLN:189
possible beneficial target for the management of coronavirus. are the amino acid residues participating in the interaction at
6LU7 (PDB ID) is the major protease in COVID-19 that has the binding pocket of SARS-CoV-2 protease (Figure 5A).
been relocated and structured in PDB recently and is Recent studies also explores that, Atovaquone significantly
available to everybody in the world (Figure 1). For the inhibited ZIKV (Zika virus) in human placental JEG3 cells in
proteolytic maturation of a virus, the protease is precisely vitro.23
significant. Protease has been studied as a possible target to
avoid the extent of contamination by inhibiting viral 5. CONCLUSION
polyprotein cleavage via blocking active sites of the protein.
This new finding of protease assembly in COVID-19, has The present study concludes that thirteen clinically approved
provided an enormous chance to recognize possible drug drugs were identified as potent inhibitors against SARS-CoV-
candidates for the management of coronavirus.20 In this study, 2 protease activity. These outcomes afford a strong
we have applied a computational approach of FDA approved foundation for the use of these drugs for CORONA
drugs in order to find a specific therapeutic possible agent management. Moreover, the dynamic ligands inhibit the
against COVID-19. We have selected 47 FDA approved catalytic response of protease by blocking the residues of
antiviral, anti-H1N1, anti-TB and antiviral drugs and retrieved amino acids intricate in the processing and strand
directly from the PubChem (National Library of Medicine). transmission reactions. The interactions by the structural
Molecular docking was accomplished with the 47 drugs model at the protease active site can afford a valuable guide
against COVID-19 structure. Molecular docking is a for additional strategies for structure-based medicines and
computational technique which aims to find non-Covalent development of new operative inhibitors of SARS-CoV-2
binding among protein (receptor) and a ligand/inhibitor (small protease. Therefore, the effect of these inhibitors can be
molecule). For recognized binding sites, the docking expects further revealed through in vitro and in vivo analysis in the
the method of interaction among a target protein and a termination of intracellular replication of coronavirus, prior
ligand. Binding energy proposes the attraction of an exact to the use as drugs in humans.
ligand and asset by which a ligand interacts with and binds to
the pocket of a target protein. A drug with a lesser binding 6. ACKNOWLEDGEMENTS
energy (∆G) is chosen as a probable drug candidate. In order
to recognize the effect of active antiviral drugs on COVID-19, All the authors are gratefully acknowledged to the
47 FDA approved antiviral compounds were selected and Department of Zoology, Kakatiya University, Warangal,
performed molecular docking against COVID-19. Docking Telangana, India for providing a Bioinformatics lab to carry
results of SARS-CoV-2 protease with selected 47 drugs out out this study. No funding to declare.
of the selected 13 showed the best docking score and were
found to be the best molecules at the target site of the 7. AUTHORS CONTRIBUTION STATEMENT
protein. Out of the 13 drugs, Maraviroc exhibited the best
docked score (-10.67 kcal/mol) with SARS-CoV-2 Rakesh Davella gathered the data and carried out the
protease.HIS:164, 41, TYR:54, ASP:187, MET:165, 49, molecular docking regard to this work. Dr. Swapna Gurrapu
LEU:167,141, PRO:168, CYS:44, 145, ARG:188, GLY:143, contributed to the interpretation of the results and data
ASN:142, ALA:191, GLN:192, 189 and THR:190 are the analysis. Pujala Shivakrishna wrote the manuscript. Dr. Estari
amino acid residues participating in the interaction at the Mamidala conceived the original idea and supervised the
binding pocket of SARS-CoV-2 protease (fig.5A).Maraviroc is research work. All authors discussed the methodology and
an effective antiretroviral agent permitted for the treatment results to the finalizing the manuscript.
of HIV-1 infection that blocks interaction among the virus and
the CCR5 co-receptor, a critical step in the HIV-1 8. CONFLICT OF INTEREST
replication. Earlier clinical trials of this drug have established
the efficacy, tolerability, and safety of maraviroc in both Conflict of interest declared none.
treatment-naive and treatment-experienced patients.21,22

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