Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2021 Dec 15;28(3):249–256. doi: 10.1007/s11655-021-3504-5

In Silico Screening of Natural Products as Potential Inhibitors of SARS-CoV-2 Using Molecular Docking Simulation

Rajib Hossain 1, Chandan Sarkar 1, Shardar Mohammad Hafiz Hassan 1, Rasel Ahmed Khan 2, Mohammad Arman 3, Pranta Ray 4, Muhammad Torequl Islam 1, Sevgi Durna Daştan 5,6, Javad Sharifi-Rad 7,✉, Zainab M Almarhoon 8, Miquel Martorell 9, William N Setzer 10,11, Daniela Calina 12
PMCID: PMC8672856  PMID: 34913151

Abstract

Objective

To explore potential natural products against severe acute respiratory syndrome coronavirus (SARS-CoV-2) via the study of structural and non-structural proteins of human coronaviruses.

Methods

In this study, we performed an in-silico survey of 25 potential natural compounds acting against SARS-CoV-2. Molecular docking studies were carried out using compounds against 3-chymotrypsin-like protease (3CLPRO), papain-like protease (PLPRO), RNA-dependent RNA polymerase (RdRp), non-structural protein (nsp), human angiotensin converting enzyme 2 receptor (hACE2R), spike glycoprotein (S protein), abelson murine leukemia viral oncogene homolog 1 (ABL1), calcineurin-nuclear factor of activated T-cells (NFAT) and transmembrane protease serine 2.

Results

Among the screened compounds, amentoflavone showed the best binding affinity with the 3CLPRO, RdRp, nsp13, nsp15, hACE2R. ABL1 and calcineurin-NFAT; berbamine with hACE2R and ABL1; cepharanthine with nsp10, nsp14, nsp16, S protein and ABL1; glucogallin with nsp15; and papyriflavonol A with PLPRO protein. Other good interacting compounds were juglanin, betulinic acid, betulonic acid, broussooflavan A, tomentin A, B and E, 7-methoxycryptopleurine, aloe emodin, quercetin, tanshinone I, tylophorine and furruginol, which also showed excellent binding affinity towards a number of target proteins. Most of these compounds showed better binding affinities towards the target proteins than the standard drugs used in this study.

Conclusion

Natural products or their derivatives may be one of the potential targets to fight against SARS-CoV-2.

Electronic Supplementary Material

Supplementary materials (Appendixes 1–6) are available in the online version of this article at DOI: 10.1007/s11655-021-3504-5

Keywords: SARS-CoV-2, natural products-derived anti-SARS-CoV-2 candidates, structural proteins, nonstructural proteins, molecular docking

Supplementary material to

11655_2021_3504_MOESM1_ESM.pdf (2.7MB, pdf)

In silico Screening of Natural Products as Potential Inhibitors of SARS-CoV-2 using Molecular Docking Simulation

Author Contributions

Conceptualization: MTI; formal analysis: CS; investigation: RH, CS, SMHH, MA and SDD; project administration: MTI and J S-R; writing-original draft: RH, RAK, PR, MTI, J S-R, and MM; Writing-review and editing: JS-R, DC, and WNS.

Conflict of Interest

The authors declare no conflict of interest.

References

  • 1.Elfiky AA, Mahdy SM, Elshemey WM. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J Med Virol. 2017;89:1040–1047. doi: 10.1002/jmv.24736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Robson B. Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus. Comput Biol Med. 2020;119:103670. doi: 10.1016/j.compbiomed.2020.103670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Calina D, Docea AO, Petrakis D, Egorov AM, Ishmukhametov AA, Gabibov AG, et al. Towards effective COVID-19 vaccines: updates, perspectives and challenges. Int J Mol Med. 2020;46:3–16. doi: 10.3892/ijmm.2020.4596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hilgenfeld R. From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J. 2014;281:4085–4096. doi: 10.1111/febs.12936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Elfiky AA. Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253:117592. doi: 10.1016/j.lfs.2020.117592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ratia K, Saikatendu KS, Santarsiero BD, Barretto N, Baker SC, Stevens RC, et al. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proc Natl Acad Sci USA. 2006;103:5717–5722. doi: 10.1073/pnas.0510851103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020;10:766–788. doi: 10.1016/j.apsb.2020.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Báez-Santos YM, St John SE, Mesecar AD. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antivir Res. 2015;115:21–38. doi: 10.1016/j.antiviral.2014.12.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Ivanov KA, Ziebuhr J. Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5′-triphosphatase activities. J Virol. 2004;78:7833–7838. doi: 10.1128/JVI.78.14.7833-7838.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Jin X, Chen Y, Sun Y, Zeng C, Wang Y, Tao J, et al. Characterization of the guanine-N7 methyltransferase activity of coronavirus nsp14 on nucleotide GTP. Virus Res. 2013;176:45–52. doi: 10.1016/j.virusres.2013.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3′-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc Natl Acad Sci USA. 2012;109:9372–9377. doi: 10.1073/pnas.1201130109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Ricagno S, Egloff M-P, Ulferts R, Coutard B, Nurizzo D, Campanacci V, et al. Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family. Proc Natl Acad Sci USA. 2006;103:11892. doi: 10.1073/pnas.0601708103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Decroly E, Imbert I, Coutard B, Bouvet M, Selisko B, Alvarez K, et al. Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2′O)-methyltransferase activity. J Virol. 2008;82:8071–8084. doi: 10.1128/JVI.00407-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.van der Hoek L, Pyrc K, Jebbink MF, Vermeulen-Oost W, Berkhout RJ, Wolthers KC, et al. Identification of a new human coronavirus. Nat Med. 2004;10:368–373. doi: 10.1038/nm1024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Berry M, Fielding BC, Gamieldien J. Potential broad spectrum inhibitors of the coronavirus 3CLPRO: a virtual screening and structure-based drug design study. Viruses. 2015;7:6642–6660. doi: 10.3390/v7122963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ortega JT, Serrano ML, Pujol FH, Rangel HR. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. 2020;19:410–417. doi: 10.17179/excli2020-1167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Zhao X, Chen D, Szabla R, Zheng M, Li G, Du P, et al. Broad and differential animal angiotensin-converting enzyme 2 receptor usage by SARS-CoV-2. J Virol. 2020;94:e00940–e00920. doi: 10.1128/JVI.00940-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Bouricha EM, Hakmi M, Akachar J, Belyamani L, Ibrahimi A. In silico analysis of ACE2 orthologues to predict animal host range with high susceptibility to SARS-CoV-2. Biotech. 2020;10:483. doi: 10.1007/s13205-020-02471-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Islam MT, Sarkar C, El-Kersh DM, Jamaddar S, Uddin SJ, Shilpi JA, et al. Natural products and their derivatives against coronavirus: a review of the non-clinical and pre-clinical data. Phytother Res. 2020;34:2471–2492. doi: 10.1002/ptr.6700. [DOI] [PubMed] [Google Scholar]
  • 20.Singh D, Gawande DY, Singh T, Poroikov V, Goel RK. Revealing pharmacodynamics of medicinal plants using in silico approach: a case study with wet lab validation. Comput Biol Med. 2014;47:1–6. doi: 10.1016/j.compbiomed.2014.01.003. [DOI] [PubMed] [Google Scholar]
  • 21.Aziz MA, Mehedi M, Akter MI, Sajon SR, Mazumder K, Rana MS. In vivo and in silico evaluation of analgesic activity of Lippia alba. Clin Phytosci. 2019;5:38. doi: 10.1186/s40816-019-0133-z. [DOI] [Google Scholar]
  • 22.Shen L, Niu J, Wang C, Huang B, Wang W, Zhu N, et al. High-throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses. J Virol. 2019;93:e00023–e00019. doi: 10.1128/JVI.00023-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Jassim SA, Naji MA. Novel antiviral agents: a medicinal plant perspective. J Appl Microbiol. 2003;95:412–427. doi: 10.1046/j.1365-2672.2003.02026.x. [DOI] [PubMed] [Google Scholar]
  • 24.Wu K, Chen L, Peng G, Zhou W, Pennell CA, Mansky LM, et al. A virus-binding hot spot on human angiotensin-converting enzyme 2 is critical for binding of two different coronaviruses. J Virol. 2011;85:5331–5337. doi: 10.1128/JVI.02274-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, et al. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL (pro) inhibition. Bioorg Med Chem. 2010;18:7940–7947. doi: 10.1016/j.bmc.2010.09.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Zhang CH, Wang YF, Liu XJ, Lu JH, Qian CW, Wan ZY, et al. Antiviral activity of cepharanthine against severe acute respiratory syndrome coronavirus in vitro. Chin Med J. 2005;118:493–496. [PubMed] [Google Scholar]
  • 27.Park JY, Yuk HJ, Ryu HW, Lim SH, Kim KS, Park KH, et al. Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem. 2017;32:504–515. doi: 10.1080/14756366.2016.1265519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, et al. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med. 2014;80:177–182. doi: 10.1055/s-0033-1360277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78:11334–11339. doi: 10.1128/JVI.78.20.11334-11339.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem. 2007;50:4087–4095. doi: 10.1021/jm070295s. [DOI] [PubMed] [Google Scholar]
  • 31.Park JY, Kim JH, Kim YM, Jeong HJ, Kim DW, Park KH, et al. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem. 2012;20:5928–5935. doi: 10.1016/j.bmc.2012.07.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Cho JK, Curtis-Long MJ, Lee KH, Kim DW, Ryu HW, Yuk HJ, et al. Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa. Bioorg Med Chem. 2013;21:3051–3057. doi: 10.1016/j.bmc.2013.03.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, et al. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antivir Res. 2005;68:36–42. doi: 10.1016/j.antiviral.2005.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Yang CW, Lee YZ, Kang IJ, Barnard DL, Jan JT, Lin D, et al. Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. Antivir Res. 2010;88:160–168. doi: 10.1016/j.antiviral.2010.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S, Gallagher T. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol. 2011;85:873–882. doi: 10.1128/JVI.02062-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020;5:eabc3582. doi: 10.1126/sciimmunol.abc3582. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

11655_2021_3504_MOESM1_ESM.pdf (2.7MB, pdf)

In silico Screening of Natural Products as Potential Inhibitors of SARS-CoV-2 using Molecular Docking Simulation

Articles from Chinese Journal of Integrative Medicine are provided here courtesy of Nature Publishing Group

RESOURCES