|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 1 | Page : 21-32 |
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Recent insights of SARS-CoV-2 potential inhibitors
Mohd Faheem1, Vinay Kumar Singh1, Abhishek Srivastava2
1 Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, Uttar Pradesh, India
2 Department of Chemistry, GLA University, Mathura, Uttar Pradesh, India
| Date of Submission | 14-Sep-2021 |
| Date of Acceptance | 26-Nov-2021 |
| Date of Web Publication | 11-Mar-2022 |
Correspondence Address:
Abhishek Srivastava
Department of Chemistry, GLA University, Mathura - 281 004, Uttar Pradesh
India
Vinay Kumar Singh
Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bbrj.bbrj_229_21
The year of 2019–2021 is emergency that the world is facing due to the spread of 2019-nCoV which has created a very critical condition in human society, known as COVID-19. The complex virus belongs to the family of coronaviridae and genera betacoronavirus and spreads through human interaction. The common symptoms observed in infected are a sudden rise in body temperature within 1st to 9th day of infection, problems around the neck and throat from the start of the infection followed by the spread of infection into the lungs that cause novel coronavirus pneumonia and kidney failure. Many of the receptor proteins of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) and target proteins of the human cells are responsible for endocytosis such as main protease or 3C-like protease, RNA polymerase, and spike protein. These proteins play a vital role in the life cycle of SARS-CoV-2. Many of the computational designed drugs and docking-based drugs are reported as anti-COVID-19. Many of the drugs show strong potent activity against this deadly virus. This study demonstrates the synthetic and computational designed approach, drugs, and compounds for the potential inhibition of the SARS-CoV-2 virus. The review will be helpful in finding a new approach of a drug as an inhibitory receptor of SARS-CoV-2.
Keywords: 3C-like protease protein, angiotensin-converting enzyme 2, coronavirus, nucleocapsid protein, papain-like protease, RNA-dependent RNA polymerase, SARS-CoV main protease
How to cite this article:
Faheem M, Singh VK, Srivastava A. Recent insights of SARS-CoV-2 potential inhibitors. Biomed Biotechnol Res J 2022;6:21-32 |
| Introduction | |  |
In the year 2019–2021, the whole world is facing an enormous health emergency due to novel coronavirus (2019-nCoV), which is named after severe acute respiratory syndrome coronavirus (SARS-CoV-2) and is commonly known as coronavirus disease COVID-19.[1] COVID-19 starts spreading in 2019 and has now become a major health issue worldwide. According to the WHO report, a novel coronavirus (SARS-CoV-2) cases are infected globally,[2],[3] and the WHO has declared coronavirus disease 2019 (COVID-19) as the sixth public health emergency of international concern on 30 January 2020. The journey of coronavirus has started in 1940 and the first case of this virus was reported in 1960.[4],[5],[6],[7]
In the coronavirus family, two species of virus infections have been reported in humans; first was Middle East Respiratory Syndrome CoV which was transmitted by civet cat to human beings and the second was SARS-CoV, where the infection was spread from camels to human beings. Now, it is SARS-CoV-2, which was supposed to spread out from the seafood market (Huanan Seafood Wholesale Market) to human beings.[8],[9] Infection of SARS-CoV-2 shows common symptoms like a high fever that comes between 1 and 9 days of infection, common cold, cough, and breathing difficulty, at the severe stage, this virus affects the kidney which causes novel coronavirus pneumonia (NCP) and ultimately may cause death.[10],[11] [Table 1] demonstrates the symptomatic difference and treatment strategy of common flu and COVID 19.
Vellingiri et al. collected detailed mechanism and action of the virus in the human cell on a single roof.[12] In this review, we have collected all the information related to the drugs which have the action against COVID-19. Recent anti-SARS-CoV-2 drugs and their target indications are listed in [Table 2]. | Table 2: Recent antisevere acute respiratory syndrome coronavirus-2 drugs and their target indications
Click here to view |
SARS-CoV-2 is a complex structure and is made up of two types of protein-structural protein, which is present over the surface of the virus in the form of spike called spike protein, glycoprotein, etc., and nonstructural protein, like 3-chymotrypsin-like protease, papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase.[24],[25],[26],[27] These four nonstructural proteins are the key to the life cycle of coronavirus. The highly hydrophobic protein envelops the main structure of this novel virus.[28] The inner structure of SARS-CoV-2 is composed of single-strand RNA and hence belongs to genera betacoronavirus.[24],[29]
Literature review data show that SARS-CoV-2 can remain in an active state on a nonliving surface until 9 days at room temperature. The research revealed that the maximum viral load probability of SARS-CoV-2 is in the saliva of the infected person.[30]
| Similarity between SARS-CoV and SARS-CoV-2 | | |
89% whole gene,[31] 82% sequence of PLpro,[32] and 96% sequence of main protease (Mpro)[31] are similar with SARS-CoV. Approximately the whole sequence of receptor angiotensin-converting enzyme 2 (ACE2)[23],[33] and 90% sequence of other enzymes are similar to SARS-CoV.[34]
| Classification and Morphology of Coronavirus | | |
According to the International Committee on Taxonomy of Viruses, coronavirus belongs to the Coronaviridae family, and this family is further divided into two subfamilies named Letovirinae and Orthocoronavirinae. The subfamily Orthocoronavirinae have four genera, namely Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.[35]
| Inhibitor Action | | |
Novel coronavirus (SARS-CoV-2) is transmitted from human to human. Some of the literature data shows that many of the receptor proteins of the SARS-CoV-2 and target proteins of the human cells are responsible for endocytosis, such as Mpro or 3C-like protease (3CLpro), RNA polymerase, and spike protein as these proteins play a very vital role in the life cycle of RNA virus. Maximum research came out with the inhibition of ACE2 because angiotensin II (AT2) receptor protein, present on the lungs cell surface is responsible for lung viral infection through binding with ACE2 that results in NCP.[36],[37],[38],[39] In this process, AP2-associated protein kinase 1 (AAK1) plays a key role in regulating and endocytosis.[20] Viral infection by SARS-CoV-2 results in a sudden rise in body temperature that is reported in between 1 and 9 days of the infection, issues around the neck region from the start of infection day, and then this infection may spread into the lungs that cause NCP and ultimately kidney failure. Recent literature shows few action plans against SARS-CoV-2 through inhibiting the activity of ACE2, Mpro or 3CLpro, RNA polymerase, spike protein, etc.[40],[41],[42],[43],[44],[45],[46],[47],[48] In this communication, we have covered recent research literature for COVID-19 and evaluated anti-SARS-CoV-2 drugs in a single roof.
| Disinfection on the Surface by the Biocidal Agent | | |
Literature shows that SARS-CoV-2 can remain in an active state on a nonliving surface until 9 days at room temperature.[49] The first aim is to prevent human-to-human surface infection because coronavirus spread by an infected person to a healthy person by entering the host cell through the mucous membrane of the nose, eyes, and mouth.[50],[51] The biocidal agents that are effective in the prevention of the spread of coronaviruses are alcohol, hydrogen peroxide, benzalkonium chloride, and sodium hypochlorite.[52] Kampf et al. reported that human coronavirus could be prevented by using sodium hypochlorite (0.1%) or ethanol (62%–71%).[49] Another report by Kampf (2020) also confirmed that sodium hypochlorite (0.1%), hydrogen peroxide (0.5%), ethanol (60%–71%) are very effective against human coronavirus and can be effectively used in the prevention of the infection against SARS-CoV-2.[53]
Xiong et al. screened out the potency of approved anti-COVID-19 drugs and natural products by establishing molecular mechanics using a CODE method (agile discovery method of drugs or natural products for emerging epidemic) in which they combine the natural product with target gene.[14] [Figure 1] demonstrates the structure of few drugs/compounds that can efficiently combine with target gene of CoV-2. Results with ribavirin exhibit the highest and strongest correlation with the SARS-CoV-2-related gene module, and other natural products such as chloroquine[32] 3,4-benzopyrene, apigenin,[31] fumaric acid, rutin,[33] kaempferol also showed higher correlation score with the SARS-CoV-2 gene and are beneficial in developing an anti-COVID-19 drug.[14] | Figure 1: Structure of drugs/compounds having potential anti-COVID-19 activity
Click here to view |
| Developed Human Angiotensin-Converting Enzyme 2 Inhibitor | | |
SARS-CoV-2 belongs to the betacoronavirus genus, enters the human cell, and infects the respiratory tract. The human ACE2 receptor is responsible for entry of coronavirus into the lower respiratory tract epithelial cell of humans.[54],[55] ACE2 is the human gene for COVID-19 infection that is why many researchers focused on the development of a drug for ACE2 inhibition for the SARS-CoV-2 prevention. The structures of drugs/compounds for ACE2 inhibition to prevent SARS-CoV-2 are presented in [Figure 2]. | Figure 2: Drugs/compounds for angiotensin-converting enzyme 2 inhibition
Click here to view |
Cui et al. reported various drug as ACE2 inhibitors such as fulvestrant (1), pirinixic acid (2), AG-013608, azathioprine (3), and staurosporine (4). Few natural (plant-based) traditional medicines such as andrographis (family: Acanthaceae), urtica (family: Urticaceae), and sambucus (Family: Adoxaceae) are also found effective against COVID-19. Cui et al. used the normalized gene expression datasets, screened by CMap and JMap software in which they set cut off of 2.0 fold change 2.0 to determine the activity of a drug.[13]
Hoffmann et al. found that transmembrane protease, serine 2 enzyme TMPRSS2 is also responsible for the infection of SARS-CoV-2 as the virus spike protein uses TMPRSS2 for entering into the cell.[56] ACE2 and TMPRSS2 both are not highly specific in the lungs. Literature reveals that the spike protein of SARS-CoV-2 weakly binds with ACE2 whereas SARS-CoV binds strongly with ACE2 receptors.[57]
Cui et al. reported angiotensin II receptor type 2 (AGTR2) as another receptor that also binds with the spike protein complex (S-protein) of SARS-CoV-2. AGTR2 has high specificity in the lungs. The docking results exhibit the strong binding affinity (energy score-15.7 kcal/mol) of AGTR2 with S-protein complex of SARS-CoV-2 in comparison to ACE2 (energy score 6.9 kcal/mol).[58] The author also reported two more genes polymeric immunoglobulin receptor and adhesion G protein-coupled receptor F1, found in high specificity in the lungs, and plays a significant role in the possible entry of SARS-CoV-2 into the human cells.[58]
SARS-CoV-2 has a spike protein, which works as a mediator between receptor and coronavirus for the possible entry of the virus into the human cells.[23] The S-protein of SARS-CoV-2 is subdivided into two units as S1 and S2. The S1 makes a large receptor-binding domain and S2 makes a stalk of the spikes on the virus capsule.[59] To stop the infection of COVID-19, Wei et al. designed some molecules using a machine intelligence-based generative network complex approach containing protease inhibitor that stops the cleavage of S-protein into S1 and S2. They also reported the binding affinity of designed molecules with SARS-CoV-2 [Table 3].[31]
Sarkar et al. published a scientific report on the docking result with some Indian medicinal plant phytochemicals with spike protein fragment with ACE2. In this report, some of the phytochemicals give excellent result and give best docking score as the chloroquine and hydroxychloroquine. The docking score of phytochemicals is hesperidin – 8.99, emodin – 6.19, anthraquinone – 6.15, rhein – 8.73, chrysin – 6.87, chloroquine – 8.98, and hydroxychloroquine – 7.82.[60]
| Main Protease or Chymotrypsin-like Protease Inhibitor | | |
3C-like proteinase or coronavirus 3CLpro or coronavirus Mpro is part of a family of enzymes found in SARS-CoV-2.[61] 3CLpro plays a vital role in the replication or duplication of RNA. Mpro enzyme of SARS-CoV-2 is similar to SARS-CoV by about 96%.[17],[31]
Zhavoronkov et al. designed some new compounds by the homology modeling-based generator, ligand-based generator, and crystal-derived pocked-based generator. These compounds are effective in SARS-CoV-2 as PLpro inhibitor and can be effectively used for the prevention of coronavirus.[29]
Hilgenfeld et al. (2020) found that alpha-keto amide derivative [Figure 3] compounds are effective against alpha and beta coronavirus. These compounds exhibit excellent activity against the Mpro of CoV. The compounds show excellent activity against anti-MERS-CoV or anti-SARS-CoV toward infected Huh7 cells.[62] Xu et al. reported docking-based model drug as Mpro inhibitor. The approved drugs such as nelfinavir, perampanel, praziquantel, eszopiclone, zopiclone, and pitavastatin show excellent binding affinity with target molecule. Among these, nelfinavir exhibits excellent binding affinity with Mpro, with binding free energy of 24.69 kcal/mole.[16] Zeng et al. also reported approved drugs as Mpro inhibitors based on the docking with Mpro of SARS-CoV. He used Mpro of SARS-CoV as the target molecule because the Mpro sequence of SARS-CoV shows 96% similarity with SARS-CoV-2. Nelfinavir, prulifloxacin, bictegravir, and tegobuvir show best activity against Mpro.[17] Using computer-based pharmacological study, Kang et al. reported that the ritonavir and lopinavir show the best activity as Mpro inhibitor and could be used as an effective drug against M protease inhibitor.[63]
Kumar et al. screened out natural drugs for the inhibitor of 3CLpro by the computational approach. They used several natural inhibitors as ligand, docked with coronavirus receptor binding site, and found that methyl tanshinonate has the best activity against spike protein.[28] Chen et al. (2020) reported 3CLpro inhibitor agent, screened by the computational approach, and found that ledipasvir[20] and velpatasvir[40] have the potent activity against 3CLpro and will be very effective in viral enzymes as an inhibitor agent [Figure 4].[64]
Several potential classes of drugs are effective against SARS-CoV-2 Mpro. Among these, indole lactam-based inhibitors, drugs from Indian traditional medicine, phytochemicals, anilid-based inhibitors, peptide-based inhibitors, and α-ketoamide inhibitors are the famous drug classes studied well.[65],[66],[67]
| RNA-dependent RNA Polymerase Inhibitor | | |
The atazanavir[42] drug, used for the treatment of antihuman immunodeficiency virus, also shows good inhibitory potency toward SARS-CoV-2 3C-like proteinase (Kd = 94.94). Using the molecule transformer-drug target interaction (MT-DTI) model, Kang et al. reported docking data, which show that atazanavir[42] binds with all replication or duplication component unit such as 2'-O-ribose methyltransferase, RNA-dependent RNA polymerase, endo RNAse, helicase, and 3'-to-5' exonuclease subunit.[63]
Nucleoside-based derivatives (approved drugs) such as ribavirin,[23] remdesivir,[43] and galidesivir[44] have the property against RNA-dependent RNA polymerase that inhibits the activity of enzyme as a result RNA synthesis is blocked. Remdesivir, an adenine derivative compound, is under trial and used 200 mg OD in the 1st day and 100 mg OD for 9 days, giving a good response as anti-COVID-19.[15],[24] Some other compounds [Table 4] are also under trial and can be used against the component of the SARS-CoV-2 complex.[24]
The chloroquine,[60] remdesivir,[43] and lopinavir[39] exhibit high potent activity against SARS-CoV-2. Chloroquine[60] is widely used for the treatment of malaria and autoimmune disease whereas some of the recent data revealed that chloroquine also has the antiviral property and can be capable to inhibit the glycosylation of cellular receptor of SARS-CoV and reduce the risk of viral infection. The research result shows that the EC90 value of chloroquine for SARS-CoV-2 is 6.90 μ M.[15]
Dang et al. analyzed some approved chemical compounds for COVID-19 on a virtual screen and find that nelfinavir,[32] bictegravir,[37] lopinavir,[39] ritonavir,[41] and sofosbuvir[48] drugs show high binding affinity with target site of SARS-CoV-2 component. They analyzed data by using docking and other deep learning model methods [Table 5].[18] | Table 5: Approved drugs, their inhibitor activity and target indication[46]
Click here to view |
| Papain-like Protease Inhibitor | | |
Angiotensin II (AT2) receptor protein, present on the lung cell surface is responsible for lung viral infection.[39] AT2 binds with ACE2 of the SARS-CoV-2 causes NCP. Endocytosis is regulated by AAK1. Stebbing et al. target AAK1 and inhibit its activity by baricitinib.[49] The drug reduces the virus entry in the cell by exhibiting an excellent binding capacity with AAK1.[20] PLpro enzyme plays an important part in the lifecycle of the RNA virus and is helpful for replication.[21] Anti-SARS drugs such as mycophenolic acid,[50] compound 45 and compound 46, and anti-HCV drugs such as grazoprevir,[53] boceprevir,[51] telaprevir[52] show potent activity against SARS-CoV-2. These drugs have the property to inhibit PLpro of SARS-CoV-2 and can be a good candidate as effective drugs for anti-NCP.[21] Lim et al. proposed that a very interesting hypothesis for the inhibiting activity of SARS-CoV-2. Zn plays a very important role in replication and viral infection. Lim et al. used an an-ejecting agent disulfiram,[47] which binds with Cys and forms disulfiram-Cys complex resulted in the loss of protein active site and finally stops the replication of RNA.[19] The structure of PLpro drugs is represented in [Figure 5].
| Inhibition of Nucleocapsid Protein | | |
In the coronavirus structure, nucleoprotein is the critical component that plays a vital role in the viral life cycle such as RNA replication or duplication, interferon inhibition, actin reorganization, host cell cycle progression, apoptosis and regulates cell metabolism like gene transcription.[68],[69],[70],[71],[72],[73] N-protein, present inside the virus structure, binds with RNA viral genome to make a complex structured virion core ribonucleoprotein having the long helical structure.[72],[73],[74],[75] Literature revealed that N-protein contains three domains, N-terminal domain (NTD), C-terminal domain (CTD), and linker region (LR). For RNA binding and oligomerization, CTDs play an important role, whereas NTDs are responsible for the RNA binding. LR is the RNA binding region and primary phosphorylation site.[72],[76],[77]
Previous study shows that the N-protein of coronavirus is used as an antiviral drug target against viral infections by blocking RNA synthesis. Hou et al. reported numerous ligands that can effectively join with the NTD of N-protein. Hou et al. developed a new N-protein inhibitor as PJ34[55] which hinders viral infection. The docking study shows that ligand binds with ribonucleotide-bonding pocket.[16] In further study compound, 48 is docked with CoV nucleocapsid protein (NP), the result shows that ligand hits with a ribonucleotide-bonding pocket of CoV NP.[78] In both ligands, polycyclic aromatic core interacts with CoV NP by π-π sacking.[78] Recently, Wagstaff et al. reported that ivermectin, which is used in parasitic infection, also exhibits nuclear transport inhibitory activity.[22] Hou et al. developed a new type of drug based on a small molecule protein–protein interaction stabilizer exhibiting antiviral activity. 5-benzyloxygramin[56] is used as a stabilizer that stabilizes the N-NTD dimers through simultaneous hydrophobic interactions.[76] The strategy of developing a new drug has been useful in the future to develop anti-COVID-19. Many of the research already reported that pyrimidone derivatives have the potential against viral infection.[79],[80] Medhi et al. chose two nitrogen atoms containing dione derivatives from the zinc database and performed docking with N-protein of SARS-CoV. The docking ability of theophylline[57] 3,4-dihydropyrimidone[58] and their derivative were evaluated by the computational method. These molecules have the ability to bind with the RNA binding region and inhibit RNA binding to the NTD of N-protein.[79],[81],[82],[83],[84],[85] Theophylline is also used in therapy for respiratory diseases. [Figure 6] represents the structure of drugs/compounds exhibiting NP inhibition.
| Anti-Novel Coronavirus Pneumonia Drugs | | |
Wang et al. reported some natural drugs as anti-NCP on behalf of docking with ACE2 and Mpro.[10] In this research, 38 Chinese patent drugs are reported as ACE2 inhibitors and Mpro inhibitors. Out of which 10 compound screened out by the computational method name as hesperidin[17] (docking score with two receptor Mpro-8.5, ACE-11.4), saikosaponin A[62] (Mpro-8.8, ACE2-11), rutin[61] (Mpro-8.9, ACE2-10.7), corosolic acid[63] (Mpro-8.8, ACE-10.2), verbascoside[64] (Mpro-8.4, ACE-10.6), baicalin[16] (Mpro-8.4, ACE-10.5), glycyrrhizin[65] (Mpro-8.9, ACE-9.9), mulberroside A[66] (Mpro-7.7, ACE-11), cynaroside[67] (Mpro-8.4, ACE2-10.2), and bilirubin[15] (Mpro-7.8, ACE-10.7) give the best docking score and bind with both ACE2 receptor and viral Mpro receptor.[10] Structure of some important anti-NCP drugs/compounds is represented in [Figure 7].
| Conclusion | | |
At present, this virus is growing very fast and is spreading all over the world. Best scientific communities are working together to defeat this deadly virus and take the world toward a better tomorrow. In this review, we represent the computationally based drugs and synthetic approach mostly for the prevention of COVID-19. An infected human to a healthy human with direct contact spreads this virus, and when the virus enters into the host cell it shows, some of the common symptoms like a sudden rise in body temperature and causes NCP. Many of the computational designed drugs and docking-based drugs are reported as anti-COVID-19, and some of the drugs are undergoing trial because these drugs show strong activity against SARS-CoV-2. The components of this virus-like spike protein, helicase, proteinase, or RNA polymerase are a type of protein that is responsible for the replication of genetic material and has a significant position in the life cycle of SARS-CoV-2. Many of the other receptor proteins of the SARS-CoV-2 and target proteins on the human cells are also responsible for endocytosis, such as ACE2, Mpro, or 3CLpro, spike protein are playing a vital role in the life cycle of SARS-CoV-2. Nowadays, many researchers are working to find suitable new drugs for precluding SARS-CoV-2 and are developing new drugs to inhibit the target protein like spike protein, 3CLpro, proteinase, RNA polymerase, NP, and helicase. In this review, we have summarized and listed new and approved drugs. This review will be helpful in finding a new approach drug as an inhibitory receptor of SARS-CoV-2 structure and their life cycle.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Lai CC, Tzu PS, Wen CK, Hung JT, Po RH. Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) and corona virus disease–2019 (COVID–19) the epidemic and the challenges. Int J Antimicrob Agents 2020;55:105924.  |
| 2. | |
| 3. | Tyagi I, Mahfooz Y, Kashif M, Anjum A. COVID–19: Journey so far and deep insight using crowd sourced data in India. MAPAN 2021;36:33-46. |
| 4. | Cheever FS, Joan BD, Alwin MP, Orville TB. A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin: I Isolation and biological properties of the virus. J Exp Med 1949;90:181-210. |
| 5. | Bailey OT, Pappenheimer AM, Cheever FS, Daniels JB. A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin: II. Pathology. J Exp Med 1949;90:195-212. |
| 6. | Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today 2020;25:668-88. |
| 7. | Shoaib MH, Ahmed FR, Sikandar M, Yousuf RI, Saleem MT. A journey from SARS-CoV-2 to COVID-19 and beyond: A comprehensive insight of epidemiology, diagnosis, pathogenesis, and overview of the progress into its therapeutic management. Front Pharmacol 2021;12:576448. |
| 8. | Chen J. Pathogenicity and transmissibility of 2019–nCoV – A quick overview and comparison with other emerging viruses. Microbes Infect 2020;22:69-71. |
| 9. | Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74. |
| 10. | Yan Y, Shen X, Cao Y, Zhang J, Wang Y, Cheng Y. Discovery of anti–2019–nCoV agents from 38 Chinese patent drugs toward respiratory diseases via docking screening. 2020. Preprints 2020; 1-26. |
| 11. | Johansson MA, Quandelacy TM, Kada S, Prasad PV, Steele M, Brooks JT, et al. SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Netw Open 2021;4:e2035057. |
| 12. | Vellingiri B, Jayaramayya K, Iyer M, Narayanasamy A, Govindasamy V, Giridharan B, et al. COVID–19: A promising cure for the global panic. Sci Total Environ 2020;725:138277. |
| 13. | Cui Q, Huang C, Ji X, Zhang W, Zhang F, Wang L. Possible Inhibitors of ACE2, the Receptor of 2019–nCoV. 2020. Preprints 2020;1-11. |
| 14. | Quan Y, Liang F, Xiong J. aCODE: Agile discovery of drugs and natural products for emerging epidemic 2019–ncov based on computational pharmacology. Preprints 2020. |
| 15. | Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. |
| 16. | Xu Z, Peng C, Shi Y, Zhu Z, Mu K, Wang X, Zhu W. Nelfinavir was predicted to be a potential inhibitor of 2019–nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation. bioRxiv 2020;1-20. |
| 17. | Li Y, Zhang J, Wang N, Li H, Shi Y, Guo G, et al. Therapeutic drugs targeting 2019–ncov main protease by high–throughput screening. bioRxiv 2020;1-16. |
| 18. | Xu X, Dang Z. Promising Inhibitor for 2019–nCoV in drug development. OSF 2020;1-11. |
| 19. | Sargsyan K, Lin CC, Chen T, Grauffel C, Chen YP, Yang WZ, et al. Multi–targeting of functional cysteines in multiple conserved SARS–CoV–2 domains by clinically safe Zn–ejectors. Chem Sci 2020;11:9904-9. |
| 20. | Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020;395:e30-1. |
| 21. | Elfiky A, Ibrahim NS. Anti–SARS and anti–HCV drugs repurposing against the Papain–like protease of the newly emerged coronavirus (2019–nCoV). Res Sq 2020;1-17. |
| 22. | Caly, L, Druce, JD, Catton, MG, Jans, DA, Wagstaff, KM. The FDA–approved drug ivermectin inhibits the replication of SARS–CoV–2 in vitro. Antivir Res 2020;178:104787. |
| 23. | Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016;3:237-61. |
| 24. | Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020;19:149-50. |
| 25. | Bhat EA, Khan J, Sajjad N, Ali A, Aldakeel FM, Mateen A, et al. SARS-CoV-2: Insight in genome structure, pathogenesis and viral receptor binding analysis – An updated review. Int Immunopharmacol 2021;95:107493. |
| 26. | Poonam B, Gill PK. Coronavirus: History, genome structure and pathogenesis. Coronaviruses 2021;2:325-38. |
| 27. | Kadam SB, Sukhramani GS, Bishnoi P, Pable AA, Barvkar VT. SARS-CoV-2, the pandemic coronavirus: Molecular and structural insights. J Basic Microbiol 2021;61:180-202. |
| 28. | Kumar S. Drug and vaccine design against novel coronavirus (2019–nCoV) spike protein through computational approach. Preprints 2020;1-16. |
| 29. | Zhavoronkov A, Aladinskiy V, Zhebrak A, Zagribelnyy B, Terentiev V, Bezrukov DS, et al. Potential COVID–2019 3C–like protease inhibitors designed using generative deep learning approaches. ChemRxiv 2021;1-18. |
| 30. | To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JM, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020;71:841-3. |
| 31. | Gao K, Nguyen DD, Wang R, Wei GW. Machine intelligence design of 2019-nCoV drugs. bioRxiv 2020;bioRxiv 2020;1-16. |
| 32. | Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 1997;25:3389-402. |
| 33. | Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for lineage B β–coronaviruses, including 2019–nCoV. Nat Microbiol 2020;5:562-9. |
| 34. | Morse JS, Lalonde T, Xu S, Liu WR. Learning from the past: Possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembiochem 2020;21:730-8. |
| 35. | |
| 36. | Ratre YK, Kahar N, Bhaskar LVKS, Bhattacharya A, Verma HK. Molecular mechanism, diagnosis, and potential treatment for novel coronavirus (COVID-19): A current literature review and perspective. 3 Biotech 2021;11:94. |
| 37. | Alsobaie S. Understanding the molecular biology of SARS-CoV-2 and the COVID-19 pandemic: A review. Infect Drug Resist 2021;14:2259-68. |
| 38. | Boopathi S, Poma AB, Kolandaivel P. Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. J Biomol Struc Dyn 2021;39:3409-18. |
| 39. | Segler MHS, Preuss M, Waller MP. Planning chemical syntheses with deep neural networks and symbolic AI. Nature 2018;555:604-10. |
| 40. | Sukhatme VP, Reiersen AM, Vayttaden SJ, Sukhatme VV. Fluvoxamine: A review of Its mechanism of action and Its role in COVID-19. Front Pharmacol 2021;12:652688. |
| 41. | Cascella M, Rajnik M, Aleem A, Dulebohn SC, Napoli RD. Features, Evaluation, and Treatment of Coronavirus (COVID–19). USA: StatPearls Publishing; 2021. |
| 42. | Jena NR. Drug targets, mechanisms of drug action, and therapeutics against SARS–CoV–2. Chem Phy Impact 2021;2:100011. |
| 43. | Mir JM, Maurya RC. Nitric oxide as a therapeutic option for COVID–19 treatment: A concise perspective. New J Chem 2021;45:1774-84. |
| 44. | Elekhnawy E, Kamar AA, Sonbol F. Present and future treatment strategies for coronavirus disease 2019. Futur J Pharm Sci 2021;7:84. |
| 45. | Kausar S, Khan FS, Ur Rehman MI, Akram M, Riaz M, Rasool G, et al. A review: Mechanism of action of antiviral drugs. Int J Immunopath Pharmacol 2021;35:1-12. |
| 46. | Trougakos IP, Stamatelopoulos K, Terpos E, Tistislonis O, Aivalioti E, Paraskevis D, et al. Insights to SARS–CoV–2 life cycle, pathophysiology, and rationalized treatments that target COVID–19 clinical complications. J Biomed Sci 2021;28:9. |
| 47. | Song LG, Xie QX, Lao HL, Lv ZY. Human coronaviruses and therapeutic drug discovery. Infect Dis Poverty 2021;10:28. |
| 48. | Zhu Q, Zhang Y, Wang L, Yao X, Wu D, Cheng J, et al. Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Antiviral Res 2021;187:105015. |
| 49. | Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents. J Hosp Infect 2020;104:246-51. |
| 50. | Otter JA, Donskey C, Yezli S, Douthwaite S, Goldenberg SD, Weber DJ. Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: The possible role of dry surface contamination. J Hosp Infect 2016;92:235-50. |
| 51. | Dowell SF, Simmerman JM, Erdman DD, Wu JS, Chaovavanich A, Javadi M, et al. Severe acute respiratory syndrome coronavirus on hospital surfaces. Clin Infect Dis 2004;39:652-7. |
| 52. | Geller C, Varbanov M, Duval RE. Human coronaviruses: Insights into environmental resistance and its influence on the development of new antiseptic strategies. Viruses 2012;4:3044-68. |
| 53. | Kampf G. Potential role of inanimate surfaces for the spread of coronaviruses and their inactivation with disinfectant agents. Infect Prev Prac 2020;2:100044. |
| 54. | Perlman S. Another Decade, Another Coronavirus. N Engl J Med 2020;382:760-2. |
| 55. | Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020;5:562-9. |
| 56. | Hoffmann M, Kleine WH, Krueger N, Mueller MA, Drosten C, Pohlmann S. The novel coronavirus 2019 (2019–nCoV) uses the SARS–coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv 2020;1-23. |
| 57. | Dong N, Yang X, Ye L, Chen K, Chan EW, Yang M, et al. Genomic and protein structure modelling analysis depicts the origin and infectivity of 2019–nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China. F1000Research 2020;9:121. |
| 58. | Cui C, Huang C, Zho W, Ji X, Zhang F, Wang L, et al. AGTR2, one possible novel key gene for the entry of 2019–ncov into human cells. IEEE/ACM trans. Comput Biol Bioinform 2021;18:1230-3. |
| 59. | Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1-23. |
| 60. | Basu A, Sarkar A, Maulik U. Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2. Sci Rep 2020;10:1-15. |
| 61. | Fan K, Wei P, Feng Q, Chen S, Huang C, Ma L, et al. Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C–like proteinase. J Biol Chem 2004;279:1637-42. |
| 62. | Zhang L, Lin D, Kusov Y, Nian Y, Ma Q, Wang J, et al. Alpha–ketoamides as broad–spectrum inhibitors of coronavirus and enterovirus replication structure–based design, synthesis, and activity assessment. J Med Chem 2020;63:4562-78. |
| 63. | Beck BR, Shin B, Choi Y, Park S, Kang K. Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS–CoV–2) through a drug–target interaction deep learning model. Comput Struct Biotec J 2020;18:784-90. |
| 64. | Chen YW, Yiu CP, Wong KY. Prediction of the 2019–nCoV 3C–like protease (3CLpro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug–repurposing candidates. F1000Research 2020;9:129. |
| 65. | Mengist HM, Dilnessa T, Jin T. Structural basis of potential inhibitors targeting SARS-CoV-2 main protease. Front Chem 2021;9:622898. |
| 66. | Dampalla CS, Zheng J, Perera KD, Wong LR, Meyerholz DK, Nguyen HN. Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS–CoV–2 infection. Natl Acad Sci USA 2021;118:e2101555118. |
| 67. | Nguyen TT, Jung JH, Kim MK, Lim S, Choi JM, Chung B, et al. The inhibitory effects of plant derivate polyphenols on the main protease of SARS coronavirus 2 and their structure-activity relationship. Molecules 2021;26:1924. |
| 68. | Hsieh PK, Chang SC, Huang CC, Lee TT, Hsiao CW, Kou YH, et al. Assembly of severe acute respiratory syndrome coronavirus RNA packaging signal into virus-like particles is nucleocapsid dependent. J Virol 2005;79:13848-55. |
| 69. | Kopecky-Bromberg SA, Martínez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol 2007;81:548-57. |
| 70. | Du L, Zhao G, Lin Y, Chan C, He Y, Jiang S, et al. Priming with rAAV encoding RBD of SARS-CoV S protein and boosting with RBD-specific peptides for T cell epitopes elevated humoral and cellular immune responses against SARS-CoV infection. Vaccine 2008;26:1644-51. |
| 71. | Surjit M, Liu B, Chow VT, Lal SK. The nucleocapsid protein of severe acute respiratory syndrome–coronavirus inhibits the activity of cyclin–cyclin–dependent kinase complex and blocks S phase progression in mammalian cells. J Biol Chem 2006;281:10669-81. |
| 72. | Chang CK, Lo SC, Wang YS, Hou MH. Recent insights into the development of therapeutics against coronavirus diseases by targeting N protein. Drug Discov Today 2016;21:562-72. |
| 73. | Liu X, Verma A, Garcia G, Ramage H, Myers RL, Lucas A, et al. Targeting the coronavirus nucleocapsid protein through GSK–3 inhibition. medRxiv 2021;1-46. |
| 74. | Masters PS, Parker MM, Ricard CS, Duchala C, Frana MF, Holmes KV, et al. Structure and function studies of the nucleocapsid protein of mouse hepatitis virus. Adv Exp Med Biol 1990;276:239-46. |
| 75. | Masters PS, Sturman LS. Background paper. Functions of the coronavirus nucleocapsid protein. Adv Exp Med Biol 1990;276:235-8. |
| 76. | Lin SM, Lin SC, Hsu JN, Chang CK, Chien CM, Wang YS, et al. Structure–based stabilization of non–native protein–protein interactions of coronavirus nucleocapsid proteins in antiviral drug design. J Med Chem 2020;63:3131-41. |
| 77. | Lin SY, Liu CL, Chang YM, Zhao J, Perlman S, Hou MH. Structural basis for the identification of the N–terminal domain of coronavirus nucleocapsid protein as an antiviral target. J Med Chem 2014;57:2247-57. |
| 78. | Chang CK, Jeyachandran S, Hu NJ, Liu CL, Lin SY, Wang YS, et al. Structure-based virtual screening and experimental validation of the discovery of inhibitors targeted towards the human coronavirus nucleocapsid protein. Mol Biosyst 2016;12:59-66. |
| 79. | Sarma P, Sekhar N, Prajapat M, Avti P, Kaur H, Kumar S, et al. In–silico homology assisted identification of inhibitor of RNA binding against 2019–nCoV N–protein (N terminal domain). J Biomol Struct Dyn 2020;38:2724-32. |
| 80. | Faheem M, Rathaur A, Pandey A, Singh VK, Tiwari AK. A review on the modern synthetic approach of benzimidazole candidate. Chem Select 2020; 5:3981-94. |
| 81. | Bhatia V, Agarwal N, Biswas BA. Multipronged strategy operationalized to combat the COVID-19 pandemic in India. Biomed Biotechnol Res J 2020;4:83-92. [Full text] |
| 82. | Al-Kuraishy HM, Al-Naimi MS, Lungnier C M, Al-Gareeb AI. Macrolides and COVID-19: An optimum premise. Biomed Biotechnol Res 2020;4:189-92. |
| 83. | Kadhim AS, Abdullah YJ. Serum levels of interleukin-6, ferritin, C-reactive protein, lactate dehydrogenase, D-dimer, and count of lymphocytes and neutrophils in COVID-19 patients: Its correlation to the disease severity. Biomed Biotechnol Res 2021;5:69-73. |
| 84. | Velayati AA, Farnia P, Besharati S, Farnia P, Ghanavi J. The importance of genomic changes of SARS-CoV-2 and its comparison with Iranian-reported COVID-19 sequencing; Whether each country has to design its treatment and vaccine production. Biomed Biotechnol Res 2020;4:13-8. |
| 85. | Mantha M, Suvvari T, Corriero A. 2-Deoxy-D-glucose as an armament against COVID-19: The key to return to normality? Biomed Biotechnol Res 2021;5:347-8. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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