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Review article
a r t i c l e i n f o a b s t r a c t
Article history: The ongoing novel coronavirus disease (COVID-19) pandemic makes us painfully perceive that our bullet
Received 19 May 2020 shells are blank so far for fighting against severe human coronavirus (HCoV). In spite of vast research
Received in revised form work, it is crystal clear that the evident does not warrant the commercial blossoming of anti-HCoV drugs.
9 June 2020
In this circumstance, drug repurposing and/or screening of databases are the only fastest option. This
Accepted 9 June 2020
Available online 12 June 2020
study is an initiative to recapitulate the medicinal chemistry of severe acute respiratory syndrome
(SARS)-CoV-2 (SARS-CoV-2). The aim is to present an exquisite delineation of the current research from
the perspective of a medicinal chemist to allow the rapid development of anti-SARS-CoV-2 agents.
Keywords:
COVID-19
© 2020 Elsevier Masson SAS. All rights reserved.
SARS-CoV-2
Anti-HCoV agent
Drug repurposing
Target based screening
Molecular modelling
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Targets for therapeutic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Molecular modeling and in silico virtual screening against SARS-CoV-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Targeting receptor binding domain (RBD)/spike protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2. Targeting N protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3. Targeting E protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.4. Targeting chymotrypsin-like protease (3CLpro) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.5. Targeting RNA dependent RNA polymerase (RdRp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.6. Targeting multiple proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. What efforts are taken to identify anti-SARS-CoV-2 agents? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. Introduction belongs to the family Coronaviridae which comes under the order
Nidovirales [3,4]. CoVs are classified into four genera: Alphacor-
Coronaviruses (CoVs) typically cause mild to severe respiratory onavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.
and intestinal infections in mammals, including humans [1,2]. It The first two genera (i.e., alpha- and betacoronavirus mainly infect
mammals, whereas, gammacoronaviruses and deltacoronaviruses
foul avian species.
* Corresponding author. More than 60 years have passed since the identification of first
E-mail addresses: [email protected], skabdulamin.rs@
human CoV (HCoV) was documented as a respiratory tract
jadavpuruniversity.in (S.A. Amin), [email protected] (T. Jha).
https://doi.org/10.1016/j.ejmech.2020.112559
0223-5234/© 2020 Elsevier Masson SAS. All rights reserved.
2 S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559
Table 1
Different types of human coronavirus (HCoVs).
Fig. 2. Schematic plot of the SARS-CoV-2 genome and proteome showing different polyproteins (pp1a and pp1b) along with the structural and accessory proteins. Abbreviations
used are: PL2-Pro, papain-like protease; 3CLpro, virus main protease; RdRp, RNA-dependent RNA polymerase; Helicase, Zn2þ-dependent helicase; S protein, spike protein; E,
envelope glycoprotein; M, matrix; N, nucleocapsid; PDB, protein data bank.
Table 2
List of reported crystal structures of SARS-CoV-2 as available from Protein Data Bank (April, 2020).
Chimeric receptor-binding domain complexed with its receptor human ACE2 6VW1 Deposited: 2020-02-18 X-RAY DIFFRACTION
Released: 2020-03-04 Resolution: 2.68 Å
Spike receptor-binding domain bound with ACE2 6M0J Deposited: 2020-02-21 X-RAY DIFFRACTION
Released: 2020-03-18 Resolution: 2.45 Å
Receptor binding domain in complex with human antibody CR3022 6W41 Deposited: 2020-03-09 X-RAY DIFFRACTION
Released: 2020-03-25 Resolution: 3.08 Å
receptor binding domain in complex with CR3022 Fab 6YLA Deposited: 2020-04-06 X-RAY DIFFRACTION
Released: 2020-04-15 Resolution: 2.42 Å
SARS-Cov-2 RNA-dependent RNA polymerase in complex with cofactors 6M71 Deposited: 2020-03-16 ELECTRON MICROSCOPY
Released: 2020-04-01 Resolution: 2.90 Å
Crystal Structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES 6WCF Deposited: 2020-03-30 X-RAY DIFFRACTION
Released: 2020-04-15 Resolution: 1.06 Å
SARS-CoV-2 3CL protease (3CL pro) in complex with a novel inhibitor 6M2N Deposited: 2020-02-28 X-RAY DIFFRACTION
Released: 2020-04-15 Resolution: 2.20 Å
Peptide-bound SARS-CoV-2 Nsp9 RNA-replicase 6W9Q Deposited: 2020-03-23 X-RAY DIFFRACTION
Released: 2020-04-08 Resolution: 2.05 Å
The N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein 6YI3 Deposited: 2020-03-31 SOLUTION NMR
Released: 2020-04-08
The crystal structure of papain-like protease of SARS-CoV-2 6W9C Deposited: 2020-03-22 X-RAY DIFFRACTION
Released: 2020-04-01 Resolution: 2.70 Å
The crystal structure of COVID-19 main protease in complex with an inhibitor N3 6LU7 Deposited: 2020-01-26 X-RAY DIFFRACTION
Released: 2020-02-05 Resolution: 2.16 Å
Crystal Structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with AMP 6W6Y Deposited: 2020-03-18 X-RAY DIFFRACTION
Released: 2020-03-25 Resolution: 1.45 Å
The 1.9 A Crystal Structure of NSP15 Endoribonuclease from SARS-CoV-2 in the Complex with a Citrate 6W01 Deposited: 2020-02-28 X-RAY DIFFRACTION
Released: 2020-03-11
Crystal structure of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2 6VYO Deposited: 2020-02-27 X-RAY DIFFRACTION
Released: 2020-03-11 Resolution: 1.70 Å
SARS-CoV-2 spike ectodomain structure (open state) 6VYB Deposited: 2020-02-25 ELECTRON MICROSCOPY
Released: 2020-03-11 Resolution: 3.20 Å
The 2019-nCoV RBD/ACE2-B0AT1 complex 6M17 Deposited: 2020-02-24 ELECTRON MICROSCOPY
Released: 2020-03-11 Resolution: 2.90 Å
Crystal Structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 6VXS Deposited: 2020-02-24 X-RAY DIFFRACTION
Released: 2020-03-04 Resolution: 2.03 Å
Crystal Structure of NSP15 Endoribonuclease from SARS-CoV-2. 6VWW Deposited: 2020-02-20 X-RAY DIFFRACTION
Released: 2020-03-04 Resolution: 2.20 Å
The crystal structure of papain-like protease of SARS-CoV-2 6W9C Deposited: 2020-03-22 X-RAY DIFFRACTION
Released: 2020-04-01 Resolution: 2.70 Å
4 S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559
entry of viral genomes into host cells (Fig. 2). Researchers already proficient to identifying leads against putative targets. Five viral
identified angiotensin converting enzyme 2 (ACE2) as a functional targets are currently being considered such as receptor binding
receptor for SARS-CoV [48e51]. The crowned shaped spike glyco- domain (RBD)/Spike protein, N protein, E protein, 3CLpro and RdRp.
protein of CoVs binds directly to ACE2 on the host cells surface and
plays critically in virus infection. ACE2 is expressed widely with 3.1. Targeting receptor binding domain (RBD)/spike protein
conserved primary structures throughout the animal kingdom.
ACE2 from fish, amphibians, reptiles, birds, to mammals can Chen and co-workers [44] suggested unique structural features
potentially interact with RBD of SARS-CoV-2 [44]. Therefore, of the spike glycoprotein RBD of SARS-CoV-2. However, the RBDs of
blocking of the RBD and ACE2 interaction is an obvious therapeutic SARS-CoV and SARS-CoV-2 share 72% amino acid sequences iden-
intervention to treat diseases caused by CoVs. Specific antibodies or tity and disclose highly similar ternary structures. On the contrary,
small molecular inhibitors can disrupt the interaction of RBD with SARS-CoV-2 exhibits a distinct loop with flexible glycyl replacing
ACE2. rigid prolyl residues in SARS-CoV. Molecular modeling study
Among the set of sixteen non-structural proteins, nsp5 is unfolded that a phenylalanine moiety (Phe486) in the flexible loop
identified to play a pivotal role in the life cycle of SARS-CoV-2 involves critically in its penetration into a deep hydrophobic pocket
replication as well as maturation (Fig. 2). Being a key component, of ACE2. This observation may partially confer a stronger interac-
the nsp5 is termed as main protease (Mpro). Like other RNA viruses, tion between SARS-CoV-2 and ACE2 of the host cell. Moreover,
the functional significance of this Mpro or chymotrypsin-like pro- spike glycoprotein of SARS-CoV-2 exhibits higher binding affinity
tease (3CLpro) of SARS-CoV-2 emerges as a fascinating drug target for its receptor in comparison to other CoVs [44]. These suggest the
for the development of anti-viral agents. aggressiveness of SARS-CoV-2 than SARS-CoV-1.
Recently, the 3D structure of 3CLpro of SARS-CoV-2 was re- This observation was in line with the analysis of Xu et al. [44]
ported [1]. Like other coronaviruses Mpro, it also consists of three where the computational model of RBD domain of the SARS-CoV-2
domains. The domain I (comprising of 8e101 amino acids) and II S protein established strong interaction with human ACE2.
(102e184 amino acids) are anti-parallel b-barrels resembling the Robson [54] performed a preliminary bioinformatics studies to
chymotrypsin. Besides, the domain III (201e306 amino acids) propose a synthetic vaccine and peptidomimetic antagonist against
essentially comprehended of five a-helices and arrayed into a the Spike glycoprotein of SARS-CoV-2. The author employed Q-UEL
antiparallel globular cluster. Interestingly, a long loop region language to perform the bioinformatics approach. KRSFIEDLLFNKV
(185e200 residues) bridged domain II and III. The substrate- was identified as a well conserved sequence motif that corresponds
binding pocket of SARS-CoV-2 virus Mpro is located in a cleft be- to the known cleavage sites of the SARS virus. This sequence motif
tween domain I and II [1]. The binding site possesses a Cys-His formed the basis for design of specific synthetic vaccine epitope
catalytic dyad with other crucial amino acid residues including and peptidomimetic agent [54].
F140, L141, N142, G143, S144, M165, E166, Q189 and T190. A group of scientists from the Cairo University, Egypt predicted
The nsp12 of SARS-CoV-2 encoded viral RNA-dependent RNA COVID-19 spike binding site to a cell-surface receptor namely
polymerase (RdRp) together with co-factors nsp7 and nsp8 boasts Glucose Regulated Protein 78 (GRP78) by employing structural
polymerase activity (Fig. 2). RdRp is a pivotal enzyme in the life bioinformatics in combination with protein-protein docking [55].
cycle of all RNA viruses including CoV, human immune deficiency Firstly, a homology model of SARS-CoV-2 spike protein was built by
virus (HIV), Hepatitis C Virus (HCV) and Zika Virus (ZIKV). Gao and using SARS-CoV spike (PDB: 6ACD, chain C) as a template. Further
co-workers [40] reported the cryo-EM structure of full-length sequence and structural alignments with the Pep42 cyclic peptide
nsp12 of SARS-CoV in complex with cofactors nsp7 and nsp8. The hypothesized four cyclic region (starting and ending with cysteine
active site domain of the SARS-CoV-2 RdRp is set up by conserved residues connected by a disulfide bond) of SARS-CoV-2 spike pro-
polymerase motifs A-G in the palm domain [40]. RdRp active site is tein as possible binding sites to GRP78. The protein-protein docking
appointing two successive aspartate residues projected from a by HADDOCK software revealed the involvement of the Substrate
beta-turn structure making them surface accessible through the Binding Domain b (SBD b) of GRP78 (PDB: 5E84) and the receptor-
nucleotide channel. As configured to SARS-CoV, the RdRp of SARS- binding domain of the SARS-CoV-2 spike protein in recognition of
CoV-2 contains a larger N-terminal extension and polymerase the host cell receptor. Moreover, the favourable binding was
domain. Multiple sequence alignment (MSA) of SARS-CoV-2 RdRp observed between regions III (C391-C525) and IV (C480- C488) of
disclosed percent sequence identity against different HCoV strains SARS-CoV-2 spike protein model and GRP78. Notably, the region IV
such as the Alpha-coronavirus (229E: 48.55% and NL63: 48.79%) and was supposed to be a pivotal driving force for GRP78 binding
the Beta-coronavirus (OC43: 55.07%, HKU1: 48.16%, MERS-CoV: (predicted binding affinity: 9.8 kcal/mol). Prediction of this binding
56.76% and SARS-CoV: 90.18%). Thus, the SARS-CoV RdRp is the site sheds light on the mode of envelope protein recognition by the
closest strain to the RdRp of SARS-CoV-2 [53]. This structural in- GRP78 substrate-binding domain for future endeavours [55].
formation may furnish a basis for the design of new anti-COVID-19
agents or drug repurposing against viral proteins. 3.2. Targeting N protein
3. Molecular modeling and in silico virtual screening against In a molecular modeling study to explore potential inhibitors of
SARS-CoV-2 RNA binding to N terminal domain (NTD) of Nucleocapsid protein
(N protein), Sarma et al. [56] pointed out two potential hits namely
Novel coronavirus (COVID-19) is hardly 180 days old. Scanty ZINC000003118440 and ZINC000000146942 (Fig. 3).
knowledge about the molecular mechanisms of the disease is The authors employed two NTD structures of N proteins namely
obstructing the attempts to develop successful anti-viral agents. In 2OFZ and 1SSK. Firstly, a set of diverse compounds from Asinex and
consequence, animal models capable of mimicking the human Maybridge library were docked. Then 15 compounds for each of the
physiological responses to SARS-CoV-2 infections are sketchy so far. targets were prioritized with significant docking scores. Further
Until precise molecular and structural biology underlying SARS- MM-GBSA binding free energy, pharmacokinetic properties (Qik-
CoV-2 replication and each of the proteins’ details functions are Prop) and drug-likeness (SwissADME) as well as molecular dy-
available, bioinformatics and molecular modelling techniques are namics (MD) studies were performed to screen the compounds.
the only handy strategy. In silico virtual screening techniques are Out of these two potential hits, one compound was a theophylline
S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559 5
derivative. Since theophylline derivative is commonly used as a after 200 ns molecular dynamics studies revealed that a-helix
bronchodilator, hence, the author further screened approved and loops of E protein escapades random movement and modulates
bronchodilators against the putative N protein RNA binding site of normal ion channel activity to succour the pathogenesis in human
CoVID-19 [56]. The approved bronchodilators showed MM-GBSA and other vertebrates. Unlikely the random manoeuvre of the E
binding affinity in the following order: protein of SARS-CoV-2 gets reduced after binding with inhibitors
Formeterol > Terbutaline > Ipratropium bromide > Tiotropium [61].
Bromide > Theophylline > Salbutamol.
Recently, native or non-native protein-protein interactions 3.4. Targeting chymotrypsin-like protease (3CLpro)
(PPIs) are emerged as a target for structure-based screening of
small molecule. It may be an alternative drug design paradigm Khan et al. [62] pinpointed three FDA-approved drugs such as
which could accelerate anti-viral drug discovery against various Remdesivir, Saquinavir and Darunavir) and two small molecules
pathogens [57e59]. Since the orthostatic/allosteric stabilization of (flavone and coumarin derivatives) as possible inhibitors of 3CLpro
non-native PPIs of SARS-CoV-2 nucleocapsid protein results by target-based virtual screening. A number of 8000 compounds
abnormal protein oligomerization and finally leading to loss of viral were docked and top 700 primary hits were distinguished by sig-
activity. Scientists from National Chung Hsing University, Taiwan nificant affinities or docking scores. Then the binding interaction
acclaimed non-native PPIs of N-terminal domain of the MERS-CoV between the active site residue of 3CLpro and the selected com-
nucleocapsid protein (MERS-CoV N-NTD) [60]. They reported a pounds were extensively scrutinized using the PLIF module in MOE.
crystal structure of MERS-CoV N-NTD in a non-native dimeric Further, MD simulation and binding free energy calculations were
configuration which turned a target for virtual screening of recorded to evaluate the dynamic behaviour, stability of protein-
orthosteric stabilizers from Acros and ZINC drug databases. This ligand contact, and binding affinity of the hits [62].
finding provides valuable insight and further motivations into the Kandeel and Al-Nazawi [63] reported statistics of pairwise
design of new anti-virals based on stabilizing a non-native protein sequence comparison matrix among the main protease (Mpro) of
interaction interface of N protein [60]. CoVs. A high pairwise sequence alignment identity (96.08%) was
found between SARS-CoV-2 and SARS-CoV-1 Mpro, whereas only
3.3. Targeting E protein 51.61% identity was exposed for SARS-CoV-2 and MERS-CoV Mpro.
In consequence, the number of amino acid differences between
Gupta and co-workers [61] employed computational techniques SARS-CoV-2 and SARS-CoV-1 Mpro was only 12, while it was 153
to explore the best possible structure of the SARS-CoV-2 E protein between SARS-CoV-2 and MERS-CoV Mpro. An early virtual
present in the PDB database. The author reported that E protein of screening (VS) study of FDA approved drugs (retrieved from Sell-
SARS-CoV-2 is a pentameric protein comprised of 35 a-helices and eckchem Inc.) against the first resolved SARS-CoV-2 Mpro crystal
40 loops. Near about 8000 compounds were docked whereas 700 structure (PDB: 6LU7) was performed. That helps the repurposing
compounds were prioritized with significant affinities or docking of already approved drugs to eradicate COVID-19 [63]. FDA
scores. The docking study with E protein of SARS-CoV-2 and phy- approved drugs were de-slated and optimized using OPLS2005
tochemicals like Belachinal, Macaflavanone E &Vibsanol divulged force field by the aid of Ligprep software. Similarly, the protein was
that amino acids such as V25 and F26 play crucially in the binding optimized by protein preparation module in Maestro software
interactions. The functional behaviour of E protein of SARS-CoV-2 package (Schrodinger LLC, NY, USA). The standard precision (SP
6 S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559
docking) of Schrodinger glide docking module was employed for 3.5. Targeting RNA dependent RNA polymerase (RdRp)
VS. Depending on the highest docking score, top 20 FDA approved
drugs were highlighted including Chromocarb (a vasoprotective), A scientist from Cairo University, Egypt performed homology
Ribavirin (Anti-viral agent), Telbivudine (anti-hepatitis B virus), modelling of SARS-CoV-2 RdRp by the aid of Swiss Model, a auto-
Vitamin B12 and Nicotinamide (Vitamin), Aminophylline (Bron- mated homology modelling web server, using SARS-CoV-1 RdRp
chodilator), Triflusal (Cardiovascular drug), Bemegride (CNS stim- (PDB: 6NUR, chain A) as a template [52]. The resulted SARS-CoV-2
ulant), Aminosalicylate Sodium and Pyrazinamide RdRp homology model expressed 97.08% sequence identity to the
(Antituberculosis agents), Temozolomide (Anticancer), Meth- template. The model was validated based on the Ramachandran
azolamide (used in Glaucoma), Tioxolone (Anti-acne agent), Pro- plot which showed 100% of the residues in the allowed regions,
pylthiouracil (Antithyroid agent), Cysteamine HCl 97.5% in the most favoured region. Further, the molecular docking
(Nephropathiccystinosis), Methoxamine hydrochloride (Alpha- was employed by utilizing AutoDock Vina to test some direct-acting
adrenergic agonist), Zonisamide (Anticonvulsant), (þ,-)-Octop- antiviral (DAA) drugs including Sofosbuvir, Ribavirin, Remidisvir,
amine HCl (Adrenergic agonist), Amiloride hydrochloride IDX-184 against COVID-19 RdRp. A grid box was chosen at the
(Diuretic). SARS-CoV-2 RdRp by utilizing the AutoDock tools using x, y, z co-
Detailed scanning of the binding mode of these drugs with ordinates of 142.1, 138.7, 150.0, respectively in 30 30 30 Å di-
SARS-CoV-2 Mpro conferred that hydrophobic and hydrogen mensions. The active site aspartates (D255 and D256) were kept
bonding interactions were the main imperators for binding. Inter- flexible during the docking study. The optimization of the ligands
estingly, Telbivudine (Fig. 3), an anti-hepatitis B virus agent, bind were performed using MM3 and PM6 force field after that further
with the SARS-CoV-2 Mpro through hydrogen bond interactions optimization was carried out through B3LYP functional of Density
with amino acid residues S49 and Q189. Moreover, a broad spec- Functional Theory (DFT) based quantum mechanics. The binding
trum antiviral agent, Ribavirin (Fig. 3), interacted with the SARS- energies and interaction complexes formed after docking conferred
CoV-2 Mpro by forming hydrogen bonds with side chain amino that IDX-184, Sofosbuvir, and Ribavirin can tightly bind to the RdRp
acid residue Q189 and the backbone amino acid residue T25. of SARS-CoV-2. Interestingly, Guanosine derivative IDX-184,
Ribavirin is officially approved against respiratory syncytial virus Sofosbuvir and Ribavirin interacted with RdRp through multiple
(RSV) infection. It is also used in combination with interferon a2b hydrogen bonding. Additionally, Sofosbuvir and IDX-184 form
against hepatitis C virus. Moreover, it also exhibited potency metal interaction through the Mgþ2 with E702 and D652, respec-
against SARS-CoV infection [63]. tively. Sofosbuvir exhibit two hydrophobic interactions with
In a study to distinguish potential active herbs against 2019- D651and Y510 whereas, IDX-184 form a salt bridge D514, which
nCoV, Ma et al. [64] performed molecular docking based virtual referred for the increased stabilization of the interactions. Hence,
screening of traditional Chinese medicine database (TCMD) 2009 strong binding with SARS-CoV-2 RdRp, these agents can contradict
by CDOCKER program against 3CLpro and papain-like protease the function of RdRp in the life cycle of 2019-nCoV viruses leading
(PLpro) of SARS-CoV-2. The VS study against Mpro screened 12,322 to viral eradication [52].
active components. On the other hand, VS approach against PLpro In another study, Elfiky [67] reported SARS-CoV-2 RdRp targeted
screened 11,294 potential ingredients and representative active molecular docking study of some anti-polymerase drugs which
ingredients such as ginger ketophenol, ginkgol alcohol, ferulic acid, have been approved for use against various viruses. Not surpris-
etc. [64]. ingly, Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir
Deep docking (DD) methodology that enable fast prediction of exhibited promising binding affinity against SARS-CoV-2 RdRp.
docking scores and expand the repertoire of structure-based VS of These results were also consistence with previous one [52]. Gua-
billions of compound in a very short time. A group of scientists from nosine derivative (IDX-184), Setrobuvir, YAK has potential to block
the University of British Columbia, Canada [65] applied DD method the SARSCoV-2 strain. Since these drugs have already passed the
to screen 1.3 billion compounds from ZINC15 library and recog- ADME and toxicity measurements these may be used as a new
nized top 1000 hits against Mpro of SARS-CoV-2 (PDB: 6LU7). Upon therapeutic drug candidate against SARS-CoV-2.
careful observation of the interaction between ZINC000541677852 Lung and co-workers [68] identified Theaflavin, a polyphenolic
(Fig. 3) and SARS-CoV-2 Mpro conferred that the P1, P2 and P3 constituent present in black tea, against RdRp after screening
groups occupied the binding pocket by forming hydrophobic in- eighty-three chemical structures from traditional Chinese medici-
teractions. In addition, it formed hydrogen bond interactions with nal compounds along with their similar structures retrieved from
three backbone amino acid residues C145, L141, H164 and one side ZINC15 database. The three-dimensional RdRp structures of SARS-
chain amino acid residue Q192 [65]. CoV-2 (NCBI: YP_009725307.1), SARS-CoV (NP_828869.1) and
Shah and co-workers [66] selected SARS-CoV-2 Mpro proteins MERS-CoV (YP_009047223.1) were modelled using Modeller 7.
(PDB: 5R7Y, 5R7Z, 5R80, 5R81, 5R82) having resolution < 2 Å, R- After molecular docking with idock (https://github.com/
Value Free < 0.30, R-Value Work < 0.25 to perform molecular HongjianLi/idock), the theaflavin showed promising binding en-
docking study of 61 anti-viral agents. The Maestro interface ergy against RdRp of SARS-CoV-2 (idock score: 9.11 kcal/mol),
(Schro€dinger Suite, LLC, NY) was used to perform the molecular MERS-CoV (idock score: 8.26 kcal/mol) and SARS-CoV (idock score:
docking study. Compounds exhibited dock score of 6.5 or less 8.03 kcal/mol). Hydrophobic interactions were found to be the
were taken as promising molecules. This comparative analysis driving force in binding. Theaflavin formed hydrogen bonds with
suggested that Asunaprevir, Indinavir, Galidesivir, Lopinavir, D452, R553 and R624 of SARS-CoV-2 RdRp. Additionally, a p-cation
Remdesivir, Ritonavir, ABT450, CGP42112A and Marboran (Methi- interaction was found with R553 [68].
sazone) interacted with >2 SARS-CoV-2 Mpro structures. Moreover,
an anti-HIV drug Lopinavir showed binding affinities for all five 3.6. Targeting multiple proteins
structures (with a dock score of less than 6.5), whereas, Indinavir
and Ritonavir (Fig. 4) interacted with 4 out of 5 proteins. Calligari et al. [69] cashed in the molecular docking technique to
In addition, Methisazone (an inhibitor of protein synthesis), examine the affinity of several inhibitors (previously developed for
CGP42112A (an angiotensin AT2 receptor agonist) and ABT450 (an another viral pathogen) to SARS-CoV-2 viral proteins (the main 3C-
inhibitor of the non-structural protein 3e4A) may be emerged as a like protease, S protein, RdRp, Nucleocapsid protein). HIV inhibitors
new hits against SARS-CoV-2 [66]. Saquinavir (DB01232: Autodock Vina Scoring 9.3 kcal/mol),
S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559 7
Indinavir (DB00224: Vina Scoring 8.7 kcal/mol), Tipranavir enzymes were forwarded to systematically analyse and screen ZINC
(DB00932: Vina Scoring 8.6 kcal/mol), Ritonavir (DB00503: Vina drug database (ZDD) along with database of traditional Chinese
Scoring 8.1 kcal/mol), Lopinavir (DB01601: Vina Scoring 8.1 kcal/ medicine and natural products and the database of commonly used
mol), Atazanavir (DB01072: Vina Scoring 8.0 kcal/mol), Nelfinavir 78 anti-viral drugs [70]. This study seems to be very interesting due
(DB00220: Vina Scoring 7.9 kcal/mol), Amprenavir (DB00701: to its deep discussions and vast target predictability. The lead
Vina Scoring 7.7 kcal/mol), Darunavir (DB01264: Vina candidates emerged from this study required in vitro and in vivo
Scoring 7.6 kcal/mol), Fosamprenavir (DB01319: Vina studies for further conformations.
Scoring 7.2 kcal/mol) were identified as promising molecules
against SARS-CoV-2 Mpro. This results were also consistence with
4. What efforts are taken to identify anti-SARS-CoV-2 agents?
hepatitis C virus (HCV) inhibitors Faldaprevir (DB11808: Vina
Scoring 8.4 kcal/mol) and Asunaprevir (DB11586: Vina
The new drug discovery and development takes more than five
Scoring 8.1 kcal/mol). Surprisingly, HCV NS3/4A protease inhibi-
to ten years of investigations as well as cost billions of dollars. Thus,
tor Simeprevir (DB06290: AutodockVina Scoring 10.0 kcal/mol)
drug repositioning is the only cheap strategy to respond immedi-
was recognized as the best Autodock Vina scoring drug. In spite of
ately. FDA-approved drugs justify safe alternatives if at least modest
HCV main protease measure very low identity with the SARS-CoV-2
anti-SARS-CoV-2 activity can be achieved. Currently, Academia and
homolog (only 7.5%), thus this finding was thunderbolt [69].
industry personnel are involved in the testing of e (i) approved
Therefore, it may be inferred that the similar topology of active site
drugs and/or (ii) drug candidates in clinical trials. The in vitro
of both proteases was the main driving force in binding of Sime-
screenings of FDA approved drugs as well as the compounds which
previr. It fitted well into the two hydrophobic pockets fringed the
are currently under clinical trials phases were well documented
catalytic dyad H41-C145 of SARS-CoV-2 Mpro. It was also fitted into
[71e77] and the need for further in vivo testing to facilitate drug
the hydrophobic loop F181-F185. Moreover, the binding of Sime-
discovery efforts against SARS-CoV-2.
previr to SARS-CoV-2 protease was anchored by three hydrogen
Nafamostat (Fig. 5) is a potent membrane fusion inhibitor of
bonding interactions with E166, G143 and N142 [69]. In the same
MERS-CoV [78]. Now, it has been found to inhibit the 2019-nCoV
article, the homology modelling of SARS-CoV-2 S protein by the aid
infection (EC50 ¼ 22.50 mM, CC50 > 100 mM, SI > 4.44).
of iTasser server was done by using SARS-CoV spike (PDB: 5WRG,
In comparison with Nafamostat, Nitazoxanide (Fig. 5) exhibited
5 58, 5XLR) as a template. Global pairwise sequence alignment
10-fold more potency to inhibit the SARS-CoV-2 infection with a
measured that SARS-CoV-2 S protein shares about 76% of its pri-
half-maximal effective concentration (EC50) ¼ 2.12 mM, half-
mary sequence with its homolog in addition an overall similarity of
maximal cytotoxic concentration (CC50) > 35.53 mM and selec-
87%. Autodock Vina molecular docking of the homology modelled
tivity index (SI) > 16.76) [72]. Besides, this is agent marketed as an
structure of S protein predicted Umifenovir (DB13609), Enfuvirtide
anti-protozoal drug [79] and also reported to possess anti-viral
(DB00109), and Pleconaril (DB05105) as potential inhibitors [69].
action against a broad range of viruses [80].
In a study to repurposing existing drugs against current
In the same article, Wang et al. [72] reported anti-COVID-19
pandemic COVID-19, Wu et al. [70] predicted some potential drugs
property of three nucleoside analogs such as Favipiravir
acting on a certain target or multiple targets of SARS-CoV-2. Bio-
(EC50 ¼ 61.88 mM; CC50 > 400 mM; SI > 6.46), Ribavirin
informatics based homology modelling was utilised to build
(EC50 ¼ 109.50 mM; CC50 > 400 mM; SI > 3.65) and Penciclovir
possible targets such as viral Mpro, PLpro, RdRp, helicase, Spike, etc.
(EC50 ¼ 95.96 mM; CC50 > 400 mM; SI > 4.17). In near future, in vivo
Next, these modelled proteins and human relative proteins
experiment is needed which will further justify the property of
including human ACE2 and type-II transmembrane serine protease
these above mentioned inhibitors of SARS-CoV-2.
8 S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559
Fig. 5. Structure and EC50 values of Nafamostat, Nitazoxanide, Favipiravir, Remdesivir and Penciclovir against SARS-CoV-2 in Vero E6 cells.
An adenosine analogue Remdesivir (Fig. 5) showed a wide array [73]. Upon introduction of a hydroxyl group into CQ resulted in
of anti-viral property from various cultured cells to nonhuman about 40% less toxic agent than CQ in animals. Both CQ and HCQ are
primate (NHP) models. This agent (GS-5734) is currently under weak bases and restrict the virus infection by- (i) triggering
clinical observation against Ebola virus infection. Broad spectrum endosomal pH which is essential for virus/cell fusion and (ii)
antiviral properties of Remdesivir have been illustrated few years interfering with the glycosylation of ACE2 receptor and spike pro-
ago [81]. Now, it has been found to effectively block SARS-CoV-2 tein of coronavirus [73]. Additionally, both CQ and HCQ obstructed
infection at low-micromolar concentration [72]. It exhibited EC50 the SARS-CoV-2 transport from early endosomes (EEs) to endoly-
of 0.77 mM against 2019-nCoV in Vero E6 cells with CC50 > 100 mM; sosomes (ELs).
selectivity index (SI) > 129.87). Remdesivir also inhibited virus Jin and co-workers [1] executed structure-assisted drug design,
infection in SARS-CoV-2 sensitive human liver cancer Huh-7 cells molecular docking, VS as well as high-throughput screening to
[72]. pinpoint new leads by targeting the 3CLpro of SARS-CoV-2. The
A widely-used anti-malarial drug Chloroquine (CQ, Fig. 6) has same study first time reported the crystal structure of SARS-CoV-2
been used for more than 70 years [82], now, found to shows clinical Mpro (PDB: 6LU7) in complex with a mechanism-based inhibitor,
potency against COVID-19. N3 (Fig. 7).
The molecular mechanism of Chloroquine against SARS-CoV is A molecular docking study with PDB: 6LU7 suggested that the
known [83,84]. Very recently, Wang et al. [72] reported time-of- ligand (i.e., Cinanserin, a serotonin antagonist, Fig. 7) adequately
addition assay that explained the function of CQ (EC50 ¼ 1.13 mM; fitted into the substrate-binding site and formed two cation-p in-
CC50 > 100 mM; SI > 88.50) at both entry as well as at post-entry teractions with His41 and Glu166 of SARS-CoV-2 Mpro. This in silico
stages of the novel corona virus infection in Vero E6 cells. observations was found in agreement with the in vitro SARS-CoV-2
The same group of researches further evaluated the in vitro anti- inhibition assay where Cinanserin exhibited IC50 value of
SARS-CoV-2 effect of Hydroxychloroquine (HCQ, Fig. 6) sulphate, a 124.93 mM. Further, a combination of SARS-CoV-2 Mpro structure-
derivative of CQ, in comparison to CQ [73]. Hydroxychloroquine based VS and high-throughput screening of more than 10,000
sulphate [85] was introduced long before, first synthesized in 1946 compounds (containing approved drugs, clinical trials compounds,
and other active compounds) picked six lead molecules as prom-
ising SARS-CoV-2 Mpro inhibitors (IC50 range: 0.67e21.4 mM).
Among these identified inhibitors, Disulfiram and Carmofur are
FDA-approved drugs, whereas Ebselen, Tideglusib, Shikonin, TDZD-
8 and PX-12 are undergoing currently in preclinical studies (Fig. 7).
Besides, Ebselen also possessed effective anti-viral activity in cell-
based assays. This interesting study done by Jin et al. [1] not only
demonstrated a robust screening strategy but also open a new
panorama to rapid discovery of lead molecules targeting SARS-CoV-
2 Mpro.
Fig. 6. Structure of Chloroquine (CQ) and Hydroxychloroquine (HCQ).
S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559 9
An attempt was made by Su and collaborators to introduce the was found promising against MERS-CoV in virus-infected Huh7
first SARS-CoV-2 MLpro crystal structure complied with a non- cells [87]. By dint of high similarity among the 3CLproteases of
covalent inhibitor named Baicalein [43]. This compound exhibited coronavirus, it is awaited that compound 11r is expected to display
promising SARS-CoV-2 Mpro inhibitory activity (IC50 ¼ 0.94 mM) good anti-viral activity against COVID-19 in near future.
along with a dose-dependent inhibition on the replication of SARS- Meanwhile, the clinical trial studies of some molecules have
CoV-2 (EC50 ¼ 1.69 mM). At the receptor binding site, Baicalein been started against COVID-19 mainly through drug repurposing
forms interaction with catalytic Glu166 and oxyanion loop residues [88]; those are depicted in Table 3.
138e145. More interestingly, it exhibited very distinct binding
mode than the other covalent or peptidomimetic 3CLpro inhibitors 5. Concluding remarks
[43].
In vitro screening of 48 drugs was screened against HCoVs The medicinal chemistry of SARS-CoV-2 infection is still in its
infection [71]. Immunofluorescence analysis with an antibody infancy, with target specific lead molecules are yet to identify. This
specific for the novel HCoV viral N protein was scored for each drug study deals with the information currently available on potential
treated cells. The dose-response curve (DRC) was developed after targets for therapeutic invention and screening of new compounds
analysing the confocal microscope images of both viral N protein or drug repurposing against SARS-CoV-2 (Fig. 8).
and cell nuclei. Remdesivir (SARS-CoV-2 IC50 ¼ 11.41 mM), Lopinavir As the 3D structure of the SARS-CoV-2 3C-like protease bears
(SARS-CoV-2 IC50 ¼ 9.12 mM) and Chloroquine (SARS-CoV-2 96% identity with its ortholog from (SARS-CoV). Interestingly, the
IC50 ¼ 7.28 mM) were used as reference drugs. Consequently, 24 residues involved in the catalysis, substrate binding and dimer-
drugs showed good activities with IC50 ranges of 0.1e10 mM. An ization of 3CLpro are 100% conserved. In addition, the polyprotein
anti-helminthic drug, Niclosamide, and a corticosteroid used to pp1ab sequences are highly similar (86% identity). Depending upon
treat asthma and allergic rhinitis, Ciclesonide, emerged as SARS- the alike substrate specificities and high identities, we are of the
CoV-2 inhibitors with IC50 of 0.28 mM and 4.33 mM, respectively. opinion that the previous progress of specific SARS-CoV inhibitors
Notably, Niclosamide reduces MERS-CoV replication by inhibiting development can undertaking a course of action on the design and
SKP2 activity leading to enhancement in autophagy [86]. Thus, a discovery of inhibitors against SARS-CoV-2. Our group have already
similar mechanism may be introduced by Niclosamide to hamper explored the structural properties important for SARS-CoV viral
SARS-CoV-2 infection [71]. 3Clike protease inhibitors [30]. Recently in a collaborative work, our
Zhang et al. [87] reported structure-based design of a-ketoa- research team suggested the implications of naphthyl derivatives
mides as broad-spectrum inhibitors of coronavirus and enterovirus against SARS-CoV-2 PLpro enzyme though in-depth ligand-recep-
replication. These showed good inhibitory properties against the tor interaction analysis [89]. We have already predicted some in-
isolated proteases, viral replicons, virus-infected Huh7 cells. Near- house glutamine-based molecules to use as a seed for drug design
equipotency against the enteroviruses, alphacoronaviruses, and and optimization against PLpro of SARS-CoV-2 [90].
betacoronaviruses was observed upon optimization of the P2 sub- In fact, some other anti-viral drugs can also be taken into
stituent of the a-ketoamides. The cyclopentylmethyl and cyclo- consideration. In this regards, target-based VS is one of the most
hexylmethyl at the P2 substituent disposed low-micromolar EC50 important approaches used for drug repurposing. The computa-
values against the three virus genera in cell cultures. Compound 11r tional analyses are not subordinate but are a right choice to enrich
10 S.A. Amin, T. Jha / European Journal of Medicinal Chemistry 201 (2020) 112559
Table 3
List of effective molecules targeting SARS-CoV-2.
the basal knowledge during the long process leading to drug Acknowledgment
development (Fig. 8). Until any clear-cut treatment approach is
prescribed for COVID-19, the use of already approved drugs is only Sk. Abdul Amin sincerely acknowledges Council of Scientific and
alternative strategy. Howbeit, relatively limited computational Industrial Research (CSIR), New Delhi, India for awarding the Senior
resource or biased in silico screening may scattered the linearity of Research Fellowship (SRF) [FILE NO.: 09/096(0967)/2019-EMR-I,
drug discovery of novel coronavirus. In the near future, the virtual Dated: 01-04-2019]. Tarun Jha is also thankful for the financial
hits may serve as a promising drug like molecule against SARS-CoV- support from RUSA 2.0 of UGC, New Delhi, India to Jadavpur Uni-
2 after details in vitro and in vivo laboratory investigations. versity, Kolkata, India. Dr. Shovanlal Gayen of Dr. Harisingh Gour
Moreover, the availability of X-ray crystal structures of the University, Sagar, India is gratefully acknowledged for his critical
important viral proteins will trigger more exhaustive docking discussion. Sk. Abdul Amin thankfully acknowledge Mr. Subhabrata
calculation of diverse chemotypes. It is crystal clear that the pre- Ghose, Mrs. Tisha Mukherjee Sarkar for their critical reading of the
vention of COVID-19 requires strong and sustainable global manuscript. We are very much thankful to the Department of
collaborative work [91]. Data sharing is exigent to fill the knowl- Pharmaceutical Technology, Jadavpur University, Kolkata, India for
edge gaps on this global pandemic. Further progress of the scien- providing the research facilities.
tific understanding regarding the structural and molecular biology
of SARS-CoV-2 will legitimate the shape of lead compounds to
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Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in Sk. Abdul Amin is a Senior Research Fellow at Department of Pharmaceutical Tech-
inhibiting SARS-CoV-2 infection in vitro, Cell Discov. 6 (2020) 16, https:// nology, Jadavpur University, Kolkata, India. He is working under the guidance of Tarun
doi.org/10.1038/s41421-020-0156-0. Jha. His research area includes design and synthesis of small molecules with anti-
[74] S. Weston, R. Haupt, J. Logue, K. Matthews, M.B. Frieman, FDA approved drugs cancer and anti-viral properties, computational chemical biology, and large-scale
with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro, BioRxiv structure-activity relationship analysis. He has published sixty two research/review ar-
(2020), https://doi.org/10.1101/2020.03.25.008482. ticles in different reputed peer-reviewed journals and three book chapters. He enjoys a
[75] L. Caly, J.D. Druce, M.G. Catton, D.A. Jans, K.M. Wagstaff, The FDA- approved good conversation on science, regional history, contemporary art and books.
Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antivir. Res.
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[76] J. Zhang, X. Ma, F. Yu, J. Liu, F. Zou, T. Pan, H. Zhang, Teicoplanin Potently Tarun Jha, a Professor at Department of Pharmaceutical Technology, Jadavpur Uni-
Blocks the Cell Entry of 2019-nCoV, BioRxiv, 2020, https://doi.org/10.1101/ versity, Kolkata, India, has supervised 16 Ph.D. students and guided nine research
2020.02.05.935387. projects funded by different organizations. He has published more than 150 research
[77] F. Touret, M. Gilles, K. Barral, A. Nougairede, E. Decroly, X.D. Lamballerie, articles in different reputed peer-reviewed journals. His research area includes design
B. Coutard, In vitro screening of a FDA approved chemical library reveals and synthesis of anti-cancer small molecules. Prof. Jha is a member of the Academic
potential inhibitors of SARS-CoV-2 replication, BioRxiv (2020), https://doi.org/ Advisory Committee of National Board of Accreditation (NBA), New Delhi, India.
10.1101/2020.04.03.023846.
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