key: cord-283956-zgrtux7i
authors: Amin, Sk. Abdul; Jha, Tarun
title: Fight against novel coronavirus: A perspective of medicinal chemists
date: 2020-06-12
journal: Eur J Med Chem
DOI: 10.1016/j.ejmech.2020.112559
sha: 
doc_id: 283956
cord_uid: zgrtux7i

The ongoing novel coronavirus disease (COVID-19) pandemic makes us painfully perceive that our bullet shells are blank so far for fighting against severe human coronavirus (HCoV). In spite of vast research work, it is crystal clear that the evident does not warrant the commercial blossoming of anti-HCoV drugs. In this circumstance, drug repurposing and/or screening of databases are the only fastest option. This 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.

Coronaviruses (CoVs) typically cause mild to severe respiratory and intestinal infections in mammals, including humans [1] [2] . It belongs to the family Coronaviridae which comes under the order Nidovirales [3] [4] . CoVs are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. The first two genera (i.e., alpha-and betacoronavirus mainly infect mammals, whereas, gammacoronaviruses and deltacoronaviruses foul avian species.

More than 60 years have passed since the identification of first human CoV (HCoV) was documented as a respiratory tract modulator [5] [6] . In December 2019, several clusters (epidemiologically associated with a seafood and animal market in Wuhan, China) of patients suffering fever, illness, severe respiratory tract infections and pneumonia of unknown origin were reported [7] [8] [9] [10] [11] [12] . This finally leaded to the isolation of a novel coronavirus (2019-nCoV) and the disease recently named as COVID-19. World Health Organization (WHO) already characterized COVID-19 as world pandemic [13] . This infection has spread over to 216 countries and territories [14] .

Before COVID-19 outbreak, there were six species of HCoVs that were reported for their association with respiratory tract infections ( Table 1) .

[ Table 1 [15] . The seventh strain of HCoV is novel coronavirus (2019-nCOV aka SARS-CoV-2) which is taxonomically belongs to the Betacoronavirus genre and possesses high nucleotide sequence similarity with SARS-CoV and MERS-CoV [16] [17] [18] [19] [20] .

SARS-CoV-2 is a positive-sense single-stranded RNA viruses surrounded by an envelope (Figure   1 ).

SARS-CoV-2, about 30,000 bp single-stranded RNA virus, utilizes host cellular components to accomplish its physiological affairs such as viral entry, the assembly and budding of virions, genomic replication, and protein synthesis, subsequently executes pathological damage to the host [21] [22] [23] . Thus, punctuating any juncture of viral life cycle by small molecules, peptides, vaccines or physical elements may potentially gain therapeutic benefit to host. Depending on several viral targets (Figure 1 ) related to the stages of viral life cycle, novel anti-viral agents may be designed and discovered. Nonetheless, different structure-based modeling techniques and numerous ligandbased computational techniques may be fruitful strategy to design newer inhibitors against SARS-CoV-2 [24] [25] [26] .

Meanwhile, the hefty menace posed by current outbreak of COVID-19, it is obvious that the scientific community is looking for effective drugs within plausible time. The coherent development and well organised strategies remains the only hope to triumph the battle against partially known SARS-CoV-2. Now, repurposing of existing anti-viral drugs based on previous ground work of closely related coronavirus and rapid screening of drug databases is one of the strategic and economic ways to eradicate COVID-19 pandemic [27] [28] [29] . The traditional bioinformatics and chemo-informatics approaches readily generated new data into SARS-CoV-2 research at an explosive pace.

Considering the severity of the spread of COVID-19, this study is in-line with the concept of finding the chemo-types to expedite the process of anti-HCoV drug discovery. Here, an exquisite picture of the recent research including target-based and biological screening is provided. We includes virtual (in silico) as well as experimental (in vitro) screening approaches in response to SARS-CoV-2 reported until April 2020. The main aim is to provide the scientific community with an overview of the medicinal chemistry of SARS-CoV-2 to allow the rapid development of antiviral agents. This work, a part of our rational drug design and discovery [30] [31] [32] [33] [34] [35] [36] , is an initiative to pave the way of anti-SARS-CoV-2 drug discovery paradigm that could help to facilitate the global efforts to fight against COVID-19.

The details structural biology of the SARS-CoV-2 virus is yet to be discovered. It contains a 30,000 bp, single-stranded positive sense RNA genome encapsulated within a membrane envelope ( Figure   1 ) [37] [38] [39] . It recruits multi-subunit replication machinery [40] . The genome of SARS-CoV-2 comprises about 30,000 nucleotides with ten Open Reading Frames (ORFs). The 3′ terminal regions encodes for several structural proteins including spike (S), membrane envelope (E) and nucleocapsid (N) proteins (Figure 1) whereas, the 5′ terminal ORF1ab responsible for two viral replicase polyproteins pp1a and pp1b. Upon proteolytic cleavage of these two viral replicase polyproteins fabricate sixteen non-structural proteins (nsp) (Figure 2 ) [37] . [ Table 2 may be placed here]

The spike glycoprotein of coronavirus is the main conciliator of entry into the host cells [45] [46] [47] [48] [49] [50] [51] [52] .

This spike glycoprotein contains (i) a large ecto-domain, (ii) a single-pass transmembrane anchor, and (iii) a short C-terminal intracellular tail [44] . The ecto-domain consists of a receptor-binding unit S1 and a membrane-fusion S2 stalk. Basically, the receptor-binding unit S1 binds to a specific cell surface receptor via its receptor binding domain (RBD), whereas the trimeric S2 fuses the viral membranes and host cell to enable the entry of viral genomes into host cells (Figure 2 ).

Researchers already identified angiotensin converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV [48] [49] [50] [51] . The crowned shaped spike glycoprotein of CoVs binds directly to ACE2 on the host cells surface and plays critically in virus infection. ACE2 is expressed widely with conserved primary structures throughout the animal kingdom. ACE2 from fish, amphibians, reptiles, birds, to mammals can potentially interact with RBD of SARS-CoV-2 [44]. Therefore, blocking of the RBD and ACE2 interaction is an obvious therapeutic intervention to treat diseases caused by CoVs. Specific antibodies or small molecular inhibitors can disrupt the interaction of RBD with ACE2.

Among the set of sixteen non-structural proteins, nsp5 is identified to play a pivotal role in the life cycle of SARS-CoV-2 replication as well as maturation (Figure 2) . Being a key component, the nsp5 is termed as main protease (Mpro). Like other RNA viruses, the functional significance of this Mpro or chymotrypsin-like protease (3CLpro) of SARS-CoV-2 emerges as an attractive drug target for the development of anti-viral agents.

Recently, the 3D structure of 3CLpro of SARS-CoV-2 was reported [1] . Like other coronaviruses Mpro, it also consists of three domains. The domain I (comprising of 8-101 amino acids) and II RdRp active site is appointing two successive aspartate residues projected from a beta-turn structure making them surface accessible through the nucleotide channel. As configured to SARS-CoV, the Robson [54] performed a preliminary bioinformatics studies to propose a synthetic vaccine and peptidomimetic antagonist against the Spike glycoprotein of SARS-CoV-2. The author employed Q-UEL language to perform the bioinformatics approach. KRSFIEDLLFNKV was identified as a well conserved sequence motif that corresponds to the known cleavage sites of the SARS virus. This sequence motif formed the basis for design of specific synthetic vaccine epitope and peptidomimetic agent [54] .

A group of scientists from the Cairo University, Egypt predicted COVID-19 spike binding site to a cell-surface receptor namely Glucose Regulated Protein 78 (GRP78) by employing structural bioinformatics in combination with protein-protein docking [55] . Notably, the region IV was supposed to be a pivotal driving force for GRP78 binding (predicted binding affinity: -9.8 kcal/mol). Prediction of this binding site sheds light on the mode of envelope protein recognition by the GRP78 substrate-binding domain for future endeavours [55] .

In a molecular modeling study to explore potential inhibitors of RNA binding to N terminal domain (NTD) of Nucleocapsid protein (N protein), Sarma et al [56] pointed out two potential hits namely ZINC000003118440 and ZINC000000146942 (Figure 3 ).

The authors employed two NTD structures of N proteins namely 2OFZ and 1SSK. Firstly, a set of diverse compounds from Asinex and Maybridge library were docked. Then 15 compounds for each of the targets were prioritized with significant docking scores. Further MM-GBSA binding free energy, pharmacokinetic properties (QikProp), drug-likeness (SwissADME) and molecular dynamics (MD) studies were performed to screen the compounds. Out of these two potential hits, one compound was a theophylline derivative. Since theophylline derivative is commonly used as a bronchodilator, hence, the author further screened approved bronchodilators against the N protein 8 RNA binding site of CoVID-19 [56] . The approved bronchodilators showed MM-GBSA binding affinity in the following order:

Formeterol> Terbutaline > Ipratropium bromide >Tiotropium Bromide > Theophylline > Salbutamol.

Recently, native or non-native protein-protein interactions (PPIs) are emerged as a target for structure-based screening of small molecule. It may be an alternative drug design paradigm which could accelerate anti-viral drug discovery against various pathogens [57] [58] [59] . Since the orthostatic/allosteric stabilization of non-native PPIs of SARS-CoV-2 nucleocapsid protein results abnormal protein oligomerizaion and finally leading to loss of viral activity. Scientists from National Chung Hsing University, Taiwan acclaimed non-native PPIs of N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD) [60] . They reported a crystal structure of MERS-CoV N-NTD in a non-native dimeric configuration which turned a target for virtual screening of orthosteric stabilizers from Acros and ZINC drug databases. This finding provides valuable insight and further motivations into the design of new anti-virals based on stabilizing a non-native protein interaction interface of N protein [60] .

Gupta and co-workers [61] employed computational techniques to explore the best possible structure of the SARS-CoV2 E protein present in the PDB database. The author reported that E protein of SARS-CoV-2 is a pentameric protein comprised of 35 α-helices and 40 loops. Near about 8,000 compounds were docked whereas 700 compounds were prioritized with significant affinities or docking scores. The docking study with E protein of SARS-CoV-2 and phytochemicals like Belachinal, Macaflavanone E &Vibsanol divulged that amino acids such as V25 and F26 play crucially in the binding interactions. The functional behaviour of E protein of SARS-CoV-2 after 200ns molecular dynamics studies revealed that α-helix and loops of E protein escapades random movement and modulates normal ion channel activity to succour the pathogenesis in human and other vertebrates. Unlikely the random manoeuvre of the E protein of SARS-CoV-2 gets reduced after binding with inhibitors [61] .

Khan et al [62] pinpointed three FDA-approved drugs such as Remdesivir, Saquinavir and Darunavir) and two small molecules (flavone and coumarin derivatives) as possible inhibitors of 3CLpro by target-based virtual screening. A number of 8,000 compounds were docked and top 700 primary hits were distinguished by significant affinities or docking scores. Then the binding interaction between the active site residue of 3CLpro and the selected compounds were extensively scrutinized using the PLIF module in MOE. Further, MD simulation and binding free energy calculations were recorded to evaluate the dynamic behaviour, stability of protein-ligand contact, and binding affinity of the hit compounds [62] .

Kandeel and Al-Nazawi [63] reported statistics of pairwise sequence comparison matrix among the main protease (Mpro) of CoVs. A high pairwise sequence alignment identity (96.08%) was found between SARS-CoV-2 and SARS-CoV-1 Mpro, whereas only 51.61% identity was exposed for SARS-CoV-2 and MERS-CoV Mpro. In consequence, the number of amino acid differences between SARS-CoV-2 and SARS-CoV-1 Mpro was only 12, while it was 153 between SARS-CoV-2 and MERS-CoV Mpro. An early virtual screening (VS) study of FDA approved drugs (retrieved from Selleckchem Inc.) against the first resolved SARS-CoV-2 Mpro crystal structure (PDB: 6LU7) was performed. That helps the repurposing of already approved drugs to eradicate COVID-19 [63] . Detailed scanning of the binding mode of these drugs with SARS-CoV-2 Mpro conferred that hydrophobic and hydrogen bonding interactions were the main imperators for binding.

Interestingly, Telbivudine (Figure 3) , an anti-hepatitis B virus agent, bind with the SARS-CoV-2

Mpro through hydrogen bond interactions with amino acid residues S49 and Q189. Moreover, a broad spectrum antiviral agent, Ribavirin (Figure 3) , interacted with the SARS-CoV-2 Mpro by forming hydrogen bonds with side chain amino acid residue Q189 and the backbone amino acid residue T25. Ribavirin is officially approved against respiratory syncytial virus (RSV) infection. It is also used in combination with interferon α2b against hepatitis C virus. Moreover, it also exhibited potency against SARS-CoV infection [63] .

In a study to distinguish potential active herbs against 2019-nCoV, Ma et al. leading to viral eradication [52] .

In another study, Elfiky [67] reported SARS-CoV-2 RdRp targeted molecular docking study of some anti-polymerase drugs which have been approved for use against various viruses. Not surprisingly, Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovirexhibited promising binding affinity against SARS-CoV-2 RdRp. These results were also consistence with previous one [52] . Guanosine derivative (IDX-184), Setrobuvir, YAK has potential to block the SARSCoV-2 strain. Since these drugs have already passed the ADME and toxicity measurements these may be used as a new therapeutic drug candidate against SARS-CoV-2.

Lung and co-workers [68] identified Theaflavin, a polyphenolic constituent present in black tea, Hydrophobic interactions were found to be the driving force in binding. Theaflavin formed hydrogen bonds with D452, R553 and R624 of SARS-CoV-2 RdRp. Additionally, a π-cation interaction was found with R553 [68] .

Calligari et al [69] AutodockVina Scoring −10.0 kcal/mol) was recognised as the best Autodock Vina scoring drug. In spite of HCV main protease measure very low identity with the SARS-CoV-2 homolog (only 7.5%), thus this finding was thunderbolt [69] . Therefore, it may be inferred that the similar topology of active site of both proteases was the main driving force in binding of Simeprevir. It fitted well into the two hydrophobic pockets fringed the catalytic dyad H41-C145 of SARS-CoV-2 Mpro. It was also fitted into the hydrophobic loop F181-F185. Moreover, the binding of Simeprevir to SARS-CoV-2 protease was anchored by three hydrogen bonding interactions with E166, G143 and N142 [69] . In the same article, the homology modelling of SARS-CoV-2 S protein by the aid of iTasser server was done by using SARS-CoV spike (PDB: 5WRG, 5 × 58, 5XLR) as a template.

Global pairwise sequence alignment measured that SARS-CoV-2 S protein shares about 76% of its primary sequence with its homolog in addition an overall similarity of 87%. Autodock Vina molecular docking of the homology modelled structure of S protein predicted Umifenovir (DB13609), Enfuvirtide (DB00109), and Pleconaril (DB05105) as potential inhibitors [69] .

In a study to repurposing existing drugs against current pandemic COVID-19, Wu et al [70] predicted some potential drugs acting on a certain target or multiple targets of SARS-CoV-2.

Bioinformatics based homology modelling was utilised to build possible targets such as viral Mpro, PLpro, RdRp, helicase, Spike, etc. Next, these modelled proteins and human relative proteins including human ACE2 and type-II transmembrane serine protease enzymes were forwarded to systematically analyse and screen ZINC drug database (ZDD) along with database of traditional Chinese medicine and natural products and the database of commonly used 78 anti-viral drugs [70] .

This study seems to be very interesting due to its deep discussions and vast target predictability.

The lead candidates emerged from this study required in vitro and in vivo studies for further conformations.

The new drug discovery and development takes more than five to ten years of investigations as well as cost billions of dollars. Thus, drug repositioning is the only cheap strategy to respond immediately. FDA-approved drugs justify safe alternatives if at least modest anti-SARS-CoV-2 activity can be achieved. Currently, Academia and industry personnel are involved in the testing of -(i) approved drugs and/or (ii) drug candidates in clinical trials. The in vitro screenings of FDA approved drugs as well as the compounds which are currently under clinical trials phases were well documented [71] [72] [73] [74] [75] [76] [77] and the need for further in vivo testing to facilitate drug discovery efforts against SARS-CoV-2.

Nafamostat ( Figure 5) is a potent membrane fusion inhibitor of MERS-CoV [78] . Now, it has been found to inhibit the 2019-nCoV infection (EC 50 Besides, this is agent marketed as an anti-protozoal drug [79] and also reported to possess antiviral against a broad range of viruses [80] .

In the same article, Wang et al [72] Remdesivir have been illustrated few years ago [81] . Now, it has been found to effectively block SARS-CoV-2 infection at low-micromolar concentration [72] . It exhibited half-maximal effective concentration (EC 50 ) of 0.77 μM against 2019-nCoV in Vero E6 cells with half cytotoxic concentration (CC 50 ) > 100 μM; selectivity index (SI) > 129.87). Remdesivir also inhibited virus infection in SARS-CoV-2 sensitive human liver cancer Huh-7 cells [72] .

A widely-used anti-malarial drug Chloroquine (CQ, Figure 6 ) has been used for more than 70 years [82] , now, found to shows clinical potency against COVID-19.

[ Figure 6 may be placed here]

The molecular mechanism of Chloroquine against SARS-CoV is known [83] [84] . Very recently, Wang et al [72] reported time-of-addition assay that explained the function of CQ (EC 50 = 1.13 μM; CC 50 > 100 μM; SI > 88.50) at both entry as well as at post-entry stages of the novel corona virus infection in Vero E6 cells.

The same group of researches further evaluated the in vitro anti-SARS-CoV-2 effect of Hydroxychloroquine (HCQ, Figure 6 ) sulphate, a derivative of CQ, in comparison to CQ [73] .

Hydroxychloroquine sulphate [85] was introduced long before, first synthesized in 1946 [73] . Upon introduction of a hydroxyl group into CQ resulted in about 40% less toxic agent than CQ in animals. Both CQ and HCQ are weak bases and restrict the virus infection by-(i) triggering endosomal pH which is essential for virus/cell fusion and (ii) interfering with the glycosylation of ACE2 receptor and spike protein of coronavirus [73] . Additionally, both CQ and HCQ obstructed the SARS-CoV-2 transport from early endosomes (EEs) to endolysosomes (ELs). interestingly, it exhibited very distinct binding mode than the other covalent or peptidomimetic 3CLpro inhibitors [43] .

In vitro screening of 48 drugs was screened against HCoVs infection [71] . Immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2 was scored for each drug treated cells. The dose-response curve (DRC) was developed after analysing the confocal microscope images of both viral N protein and cell nuclei. Remdesivir (SARS-CoV-2 IC 50 = 11.41 µM), Lopinavir (SARS-CoV-2 IC 50 = 9.12 µM) and Chloroquine (SARS-CoV-2 IC 50 = 7.28 µM) were used as reference drugs. Consequently, 24 drugs showed good activities with IC 50 ranges of 0.1 to 10 μM. An anti-helminthic drug, Niclosamide, and a corticosteroid used to treat asthma and allergic rhinitis, Ciclesonide, emerged as SARS-CoV-2 inhibitors with IC 50 of 0.28 μM and 4.33 μM, respectively. Notably, Niclosamide reduces MERS-CoV replication by inhibiting SKP2 activity leading to enhancement in autophagy [86] . Thus, a similar mechanism may be introduced by Niclosamide to hamper SARS-CoV-2 infection [71] .

Zhang et al [87] reported structure-based design, synthesis and activity assessment of α-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication. These showed good inhibitory properties against the isolated proteases, viral replicons, virus-infected Huh7 cells. Nearequipotency against the enteroviruses, alphacoronaviruses, and betacoronaviruses was observed upon optimization of the P2 substituent of the α-ketoamides. The cyclopentylmethyl and cyclohexylmethyl at the P2 substituent disposed low-micromolar EC 50 values against the three virus genera in cell cultures. Compound 11r was found promising against MERS-CoV in virus-infected Huh7 cells [87] . By dint of high similarity among the 3CLproteases of coronavirus, it is awaited that compound 11r is expected to display good anti-viral activity against COVID-19 in near future.

Meanwhile, the clinical trial studies of some molecules have been started against COVID-19 mainly through drug repurposing [88] ; those are depicted in Table 2 .

The medicinal chemistry of SARS-CoV-2 infection is still in its infancy, with target specific lead molecules are yet to identify. This study deals with the information currently available on potential targets for therapeutic invention and screening of new compounds or drug repurposing against SARS-CoV-2 (Figure 8 ).

As the 3D structure of the SARS-CoV-2 3C-like protease bears 96% identity with its ortholog from (SARS-CoV). Interestingly, the residues involved in the catalysis, substrate binding and dimerization of 3CLpro are 100% conserved. In addition, the polyprotein pp1ab sequences are highly similar (86% identity). Depending upon the alike substrate specificities and high identities, we are of the opinion that the previous progress of specific SARS-CoV inhibitors development can undertaking a course of action on the design and discovery of inhibitors against SARS-CoV-2. Our group have already explored the structural properties important for SARS-CoV viral 3Clike protease inhibitors [30] . Recently in a collaborative work, our research team suggested the implications of naphthyl derivatives against SARS-CoV-2 PLpro enzyme though in-depth ligandreceptor interaction analysis [89] . We have already predicted some in-house glutamine-based molecules to use as a seed for drug design and optimization against PLpro of SARS-CoV-2 [90].

In fact, some other anti-viral drugs can also be taken into consideration. In this regards, target-based VS is one of the most important approaches used for drug repurposing. The computational analyses are not subordinate but are a right choice to enrich the basal knowledge during the long process leading to drug development (Figure 8) . Until any clear-cut treatment approach is prescribed for COVID-19, the use of already approved drugs is only alternative strategy. Howbeit, relatively limited computational resource or biased in silico screening may scattered the linearity of drug discovery of novel coronavirus. In the near future, the virtual hits may serve as a promising drug like molecule against SARS-CoV-2 after details in vitro and in vivo laboratory investigations.

Moreover, the availability of X-ray crystal structures of the important viral proteins will trigger more exhaustive docking calculation of diverse chemotypes. It is crystal clear that the prevention of COVID-19 requires strong and sustainable global collaborative work [91] . Data sharing is exigent to fill the knowledge gaps on this global pandemic. Further progress of the scientific understanding regarding the structural and molecular biology of SARS-CoV-2 will legitimate the shape of lead compounds to achieve therapeutic goals. The development of medicinal chemistry through bioinformatics and chemo-informatics studies remains indispensable with a bit of savoir faire.

The authors have no conflict of interests. 

Sk. Abdul Amin is a Senior Research Fellow at Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. He is working under the guidance of Tarun Jha. His research area includes design and synthesis of small molecules with anti-cancer and anti-viral properties, computational chemical biology, and large-scale structure-activity relationship analysis. He has published sixty two research/review articles in different reputed peer-reviewed journals and three book chapters. He enjoys a good conversation on science, regional history, contemporary art and books.

Tarun Jha, a Professor at Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, has supervised 16 Ph.D. students and guided nine research projects funded by different organizations. He has published more than 150 research articles in different reputed peer-reviewed journals. His research area includes design and synthesis of anti-cancer small molecules. Prof. Jha is a member of the Academic Advisory Committee of National Board of Accreditation (NBA), New Delhi, India. 

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It is a challenging task to identify effective anti-COVID-19 drugs urgently. An exquisite picture of the recent research including target-based and biological screening is provided. Experimental screening approaches in response to 2019-nCoV is highlighted. It is an initiative from the perspective of a medicinal chemist to provide information about potential targets and drug repurposing against COVID-19.

The authors have no conflict of interests.