Generic placeholder image



ISSN (Print): 2666-7967
ISSN (Online): 2666-7975

Review Article (Mini-Review)

SARS-CoV-2 and its Predicted Potential Natural Inhibitors: A Review and Perspective

Author(s): Priyanka Samji*, Manoj Kumar Rajendran and Vidya P. Warrier

Volume 2 , Issue 5 , 2021

Published on: 30 August, 2020

Article ID: e260521185399 Pages: 14

DOI: 10.2174/2666796701999200831105801


SARS-CoV-2, a novel coronavirus, has caused the pneumonia outbreak in the entire world and every day, the number of cases is increasing in an exponential manner. Unfortunately, there is no clinically approved drug or vaccine specific for SARS-CoV-2 to date, and analysis of the current rate of spread of infection suggests that there is no time to wait for the approval of drugs and vaccine production. The sequence and phylogenetic analysis of SARS-CoV-2 has shown that it is very much similar to SARS/SARS-like coronaviruses and belongs to the betacoronavirus genera and bats are likely to be the native host of the SARS-CoV-2. Interestingly, the SARS-CoV-2 S protein and SARS-CoV S protein shared an almost identical 3-D structure in the RBD domain and the SARS-CoV-2 S protein was found to have a significant binding affinity to human ACE2. Further, RdRp and 3CLpro protease of SARSCoV- 2 share over 95% of sequence similarity with those of SARS-CoV. Recently, various molecular docking studies have been carried out to search for natural compounds that can target S protein, RdRp, 3CLpro, and nsp proteins of SARS-CoV-2. This review is an attempt to give a comprehensive idea of the different natural products that can be used to target SARS-CoV-2. However, further research is necessary to investigate the potential uses of these predicted SARS-CoV-2 inhibitors in combating the COVID-19 pandemic.

Keywords: Coronavirus, SARS, SARS-CoV-2, spike protein, ACE-2, phytochemicals, molecular docking.

Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020; 63(3): 457-60.
[] [PMID: 32009228]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[] [PMID: 32015507]
Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24(6): 490-502.
[] [PMID: 27012512]
Zhu N, Zhang D, Wang W, et al. China novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[] [PMID: 31978945]
Tang B, Bragazzi NL, Li Q, Tang S, Xiao Y, Wu J. An updated estimation of the risk of transmission of the novel coronavirus (2019-nCov). Infect Dis Model 2020; 5: 248-55.
[] [PMID: 32099934]
Chan JF-W, Kok K-H, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9(1): 221-36.
[] [PMID: 31987001]
Graham RL, Sparks JS, Eckerle LD, Sims AC, Denison MR. SARS coronavirus replicase proteins in pathogenesis. Virus Res 2008; 133(1): 88-100.
[] [PMID: 17397959]
Saikatendu KS, Joseph JS, Subramanian V, et al. Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1′'-phosphate dephosphorylation by a conserved domain of nsP3. Structure 2005; 13(11): 1665-75.
[] [PMID: 16271890]
Ma Y, Wu L, Shaw N, et al. Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proc Natl Acad Sci USA 2015; 112(30): 9436-41.
[] [PMID: 26159422]
Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579(7798): 265-9.
[] [PMID: 32015508]
Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat Rev Microbiol 2009; 7(3): 226-36.
[] [PMID: 19198616]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.
[] [PMID: 32142651]
Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000; 81(Pt 4): 853-79.
[] [PMID: 10725411]
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(5): 730-8.
[] [PMID: 32022370]
Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2019; 367(6483): 1260-3.
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[] [PMID: 32007145]
Dong N, Yang X, Ye L, Chen K, Chan EW-C, Chen S. Genomic and protein structure modelling analysis depicts the origin and pathogenicity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China. F1000 Res 2020; 9: 121.
Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 2006; 22(2): 195-201.
[] [PMID: 16301204]
Tai W, He L, Zhang X, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol 2020; 17(6): 613-20.
[] [PMID: 32203189]
Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020; 181(5): 1016-1035.e19.
[] [PMID: 32413319]
Huertas A, Montani D, Savale L, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J 2020; 56(1)2001634
[PMID: 32554538]
Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S. Potential inhibitor of COVID-19 main protease (M pro) from several medicinal plant compounds by molecular docking Study. Preprints 2020; p. 2020030226.
Wen CC, Kuo YH, Jan JT, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007; 50(17): 4087-95.
[] [PMID: 17663539]
Varshney KK, Varshney M, Nath B. Molecular modeling of isolated phytochemicals from ocimum sanctum towards exploring potential inhibitors of SARS coronavirus main protease and papain-like protease to treat COVID-19 Available from:
Chen H, Du Q. Potential natural compounds for preventing SARS-CoV-2 (2019-nCoV) infection Preprints 2020, 2020010358
Chen H-S, Qi S-H, Shen J-G. One-compound-multi-target: combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol 2017; 15(1): 134-56.
[] [PMID: 27334020]
Ishfaq M, Zhang W, Hu W, et al. Antagonistic effects of baicalin on Mycoplasma gallisepticum-induced inflammation and apoptosis by restoring energy metabolism in the chicken lungs. Infect Drug Resist 2019; 12: 3075-89.
[] [PMID: 31632098]
Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004; 31(1): 69-75.
[] [PMID: 15288617]
Deng YF, Aluko RE, Jin Q, Zhang Y, Yuan LJ. Inhibitory activities of baicalin against renin and angiotensin-converting enzyme. Pharm Biol 2012; 50(4): 401-6.
[] [PMID: 22136493]
Wang W, Ma X, Han J, et al. Neuroprotective effect of scutellarin on ischemic cerebral injury by down-regulating the expression of angiotensin-converting enzyme and AT1 Receptor. PLoS One 2016; 11(1): 1-17.
Lin CW, Tsai FJ, Tsai CH, et al. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68(1): 36-42.
[] [PMID: 16115693]
Takahashi S, Yoshiya T, Yoshizawa-Kumagaye K, Sugiyama T. Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean. Biomed Res 2015; 36(3): 219-24.
[] [PMID: 26106051]
Pilcher H. Liquorice may tackle SARS Available from:
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361(9374): 2045-6.
[] [PMID: 12814717]
Hoever G, Baltina L, Michaelis M, et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem 2005; 48(4): 1256-9.
[] [PMID: 15715493]
Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020; 7(1): 4.
[] [PMID: 32029004]
Narayanan N, Nair DT. Vitamin B12 may inhibit RNA-dependent-RNA polymerase activity of nsp12 from the SARS-CoV-2 virus. IUBMB Life 2020; 72(10): 2112-20.
Balkrishna A, Pokhrel S, Singh J, Varshney A. Withanone from Withania somnifera may inhibit novel coronavirus (COVID-19) entry by disrupting interactions between viral s-protein receptor binding domain and host ACE2 receptor. Available from:
Alves DS, Pérez-Fons L, Estepa A, Micol V. Membrane-related effects underlying the biological activity of the anthraquinones emodin and barbaloin. Biochem Pharmacol 2004; 68(3): 549-61.
[] [PMID: 15242821]
Liu Z, Ma N, Zhong Y, Yang ZQ. Antiviral effect of emodin from Rheum palmatum against coxsakievirus B5 and human respiratory syncytial virus in vitro. J Huazhong Univ Sci Technolog Med Sci 2015; 35(6): 916-22.
[] [PMID: 26670446]
Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res 2007; 74(2): 92-101.
[] [PMID: 16730806]
Schwarz S, Wang K, Yu W, Sun B, Schwarz W. Emodin inhibits current through SARS-associated coronavirus 3a protein. Antiviral Res 2011; 90(1): 64-9.
[] [PMID: 21356245]
Utomo RY, Ikawati M, Meiyanto E. Revealing the potency of citrus and galangal constituents to halt SARS-CoV-2 infection. Preprints Org 2020; 2: 1-8.
Salim B, Noureddine M. Identification of compounds from Nigella Sativa as new potential inhibitors of 2019 novel coronavirus (Covid-19): molecular docking study. ChemRxiv 2020; 1-12.
Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach. J Biomol Struct Dyn 2020; 0(0): 1-7. [Internet
[] [PMID: 32329419]
Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583(7816): 459-68.
[] [PMID: 32353859]
Smith M, Smith JC. Repurposing therapeutics for COVID-19: supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface Available from: Therapeutics_for_the_Wuhan_Coronavirus_nCov-2019_Supercomputer-Based_Docking_to_the_Viral_S_Protein_and_Human_ACE2_Interface/11871402?file=21962772
Lin S, Wang S, Liu M, et al. Glycosides from the stem bark of Fraxinus sieboldiana. J Nat Prod 2007; 70(5): 817-23.
[] [PMID: 17461599]
Lin S, Liu MT, Wang SJ, Li S, Yang YC, Shi JG. Coumarins from branch of Fraxinus sieboldiana and their antioxidative activity. Zhongguo Zhongyao Zazhi 2008; 33(14): 1708-10.
[PMID: 18841773]
Kim HJ, Yu YG, Park H, Lee YS. HIV gp41 binding phenolic components from Fraxinus sieboldiana var. angustata. Planta Med 2002; 68(11): 1034-6.
[] [PMID: 12451497]
Sood P, Sood RS. A review on ethnomedicinal, phytochemical and pharmacological aspects of myrica esculenta. Indian J Pharm Sci 2018; 80(1): 2-13.
Leibovitz B, Siegel BV. Diet and resistance to disease. J Am Med Assoc 1915; LXIV(12): 998.
Atherton JG, Kratzing CC, Fisher A. The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus. Arch Virol 1978; 56(3): 195-9.
[] [PMID: 205194]
Hemilä H, Douglas RM. Vitamin C and acute respiratory infections. Int J Tuberc Lung Dis 1999; 3(9): 756-61.
[PMID: 10488881]
Hemilä H. Vitamin C and SARS coronavirus. J Antimicrob Chemother 2003; 52(6): 1049-50.
[PMID: 14613951]
Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134(6): 1129-40.
[] [PMID: 16959053]
Armas LAG, Dowell S, Akhter M, et al. Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color. J Am Acad Dermatol 2007; 57(4): 588-93.
[] [PMID: 17637484]
Rockell JEP, Skeaff CM, Williams SM, Green TJ. Association between quantitative measures of skin color and plasma 25-hydroxyvitamin D. Osteoporos Int 2008; 19(11): 1639-42.
[] [PMID: 18408879]
Cantorna MT, Yu S, Bruce D. The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med 2008; 29(6): 369-75.
[] [PMID: 18561994]
Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173(5): 2909-12.
[] [PMID: 15322146]
Yuan W, Pan W, Kong J, et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282(41): 29821-30.
[] [PMID: 17690094]
Dijkman R, Jebbink MF, Deijs M, et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol 2012; 93(Pt 9): 1924-9.
[] [PMID: 22718567]
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration. UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395(10229): 1033-4.
[] [PMID: 32192578]
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 46(5): 846-8.
[] [PMID: 32125452]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[] [PMID: 31986264]
Avasarala S, Zhang F, Liu G, Wang R, London SD, London L. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS One 2013; 8(2)e57285
[] [PMID: 23437361]
Yu W-G, Xu G, Ren G-J, et al. Preventive action of curcumin in experimental acute pancreatitis in mouse. Indian J Med Res 2011; 134(5): 717-24.
[] [PMID: 22199113]
Cheppudira B, Greer A, Mares A, et al. The anti-inflammatory and analgesic activity of curcumin in a rat model of full thickness thermal injury. J Pain 2013; 14(4): S52.
Song Y, Ge W, Cai H, Zhang H. Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-κB pathway. J Cardiovasc Pharmacol Ther 2013; 18(6): 560-9.
[] [PMID: 24057864]
Sordillo PP, Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In Vivo 2015; 29: 1-4.
Chen DY, Shien JH, Tiley L, et al. Curcumin inhibits influenza virus infection and haemagglutination activity. Food Chem 2010; 119(4): 1346-51.
Chen CQ, Yu K, Yan QX, et al. Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases. Carcinogenesis 2013; 34(7): 1442-9.
[] [PMID: 23430957]
Kedzierski L, Linossi EM, Kolesnik TB, et al. Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. PLoS Pathog 2014; 10(5)e1004134
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm 2007; 4(6): 807-18.
[] [PMID: 17999464]
Gera M, Sharma N, Ghosh M, et al. Nanoformulations of curcumin: an emerging paradigm for improved remedial application. Oncotarget 2017; 8(39): 66680-98.
[] [PMID: 29029547]
Kloeshc B, Gober L, Loebsch S, Vcelar B, Helson L, Steiner G. anti-inflammatory effects of LipocurcTM on human synovial fibroblasts (SW982) and mouse macrophages (RAW264) and compared them with those of uncapsulated, free curcumin. In Vivo 2016; 30: 413-20.
Storka A, Vcelar B, Klickovic U, et al. Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans. Int J Clin Pharmacol Ther 2015; 53(1): 54-65.
[] [PMID: 25500488]
Dai Y, Chen SR, Chai L, Zhao J, Wang Y, Wang Y. Overview of pharmacological activities of Andrographis paniculata and its major compound andrographolide. Crit Rev Food Sci Nutr 2019; 59(sup1): S17-29.
[] [PMID: 30040451]
Gupta S, Mishra KP, Ganju L. Broad-spectrum antiviral properties of andrographolide. Arch Virol 2017; 162(3): 611-23.
[] [PMID: 27896563]
Seubsasana S, Pientong C, Ekalaksananan T, Thongchai S, Aromdee C. A potential andrographolide analogue against the replication of herpes simplex virus type 1 in vero cells. Med Chem 2011; 7(3): 237-44.
[] [PMID: 21486208]
Wintachai P, Kaur P, Lee RCH, et al. Activity of andrographolide against chikungunya virus infection. Sci Rep 2015; 5: 14179.
[] [PMID: 26384169]
Ramalingam S, Karupannan S, Padmanaban P, et al. Anti-dengue activity of Andrographis paniculata extracts and quantification of dengue viral inhibition by SYBR green reverse transcription polymerase chain reaction. Ayu 2018; 39(2): 87-91.
[] [PMID: 30783363]
Azzariti A, Colabufo NA, Berardi F, et al. Cyclohexylpiperazine derivative PB28, a sigma2 agonist and sigma1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol Cancer Ther 2006; 5(7): 1807-16.
[] [PMID: 16891467]
Thompson PA, Eam B, Young NP, et al. Preclinical Evaluation of eFT226, a novel, potent and selective eIF4A inhibitor with anti-tumor activity in B-Cell malignancies. Blood 2017; 130(Suppl. 1): 1530.
Radha Krishna LK, Poulose VJ, Goh C. The use of midazolam and haloperidol in cancer patients at the end of life. Singapore Med J 2012; 53(1): 62-6.
[PMID: 22252186]
Česen MH, Repnik U, Turk V, Turk B. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis 2013; 4(10): e818-.
[] [PMID: 24091661]
Carelli JD, Sethofer SG, Smith GA, et al. Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex. eLife 2015; 4e10222
Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006; 440(7083): 463-9.
[] [PMID: 16554806]
Kemp JP, Bernstein IL, Bierman CW, et al. Pemirolast, a new oral nonbronchodilator drug for chronic asthma. Ann Allergy 1992; 68(6): 488-91.
[PMID: 1610024]
D’Arcy PF. Nitrofurantoin. Drug Intell Clin Pharm 1985; 19(7-8): 540-7.
[] [PMID: 3896715]
Timmins GS, Deretic V. Mechanisms of action of isoniazid. Mol Microbiol 2006; 62(5): 1220-7.
[] [PMID: 17074073]
Ley JP, Krammer G, Reinders G, Gatfield IL, Bertram H-J. Evaluation of bitter masking flavanones from Herba Santa (Eriodictyon californicum (H. and A.) Torr., Hydrophyllaceae). J Agric Food Chem 2005; 53(15): 6061-6.
[] [PMID: 16028996]
Chen H, Muhammad I, Zhang Y, et al. Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L. Front Pharmacol 2019; 10: 1272.
[] [PMID: 31736754]
Kim DE, Min JS, Jang MS, et al. Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus oc43 infection of mrc-5 human lung cells. Biomolecules 2019; 9(11)E696
[] [PMID: 31690059]
Shih C-M, Wu C-H, Wu W-J, Hsiao Y-M, Ko J-L. Hypericin inhibits hepatitis C virus replication via deacetylation and down-regulation of heme oxygenase-1. Phytomedicine 2016; 46: 193-8.
Prasad S, Potdar V, Cherian S, Abraham P, Basu A. Transmission electron microscopy imaging of SARS-CoV-2. Indian J Med Res 2020; 2: 241-3.
Yadav PD, Potdar VA, Choudhary ML, et al. Full-genome sequences of the first two SARS-CoV-2 viruses from India. Indian J Med Res 2020; 151(2 & 3): 200-9.
[PMID: 32242873]

© 2022 Bentham Science Publishers | Privacy Policy