Generic placeholder image

Recent Patents on Biotechnology


ISSN (Print): 1872-2083
ISSN (Online): 2212-4012

Research Article

The Inhibitory Effects of the Herbals Secondary Metabolites (7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol) on COVID-19: A Molecular Docking Study

Author(s): Farshid Zargari, Mehdi Mohammadi, Alireza Nowroozi, Mohammad Hossein Morowvat, Ebrahim Nakhaei and Fatemeh Rezagholi*

Volume 18, Issue 4, 2024

Published on: 27 November, 2023

Page: [316 - 331] Pages: 16

DOI: 10.2174/0118722083246773231108045238

Price: $65


Background: Since the COVID-19 outbreak in early 2020, researchers and studies are continuing to find drugs and/or vaccines against the disease. As shown before, medicinal plants can be very good sources against viruses because of their secondary compounds which may cure diseases and help in survival of patients. There is a growing trend in the filed patents in this field.

Aims: In the present study, we test and suggest the inhibitory potential of five herbal based extracts including 7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol with antivirus activity on the models of the significant antiviral targets for COVID-19 like spike glycoprotein, Papain-like protease (PLpro), non-structural protein 15 (NSP15), RNA-dependent RNA polymerase and core protease by molecular docking study.

Methods: The Salvia rythida root was extracted, dried, and pulverized by a milling machine. The aqueous phase and the dichloromethane phase of the root extractive were separated by two-phase extraction using a separatory funnel. The separation was performed using the column chromatography method. The model of the important antivirus drug target of COVID-19 was obtained from the Protein Data Bank (PDB) and modified. TO study the binding difference between the studied molecules, the docking study was performed.

Results: These herbal compounds are extracted from Salvia rhytidea, Curcuma zeodaria, Frankincense, Peganum harmala, and Cannabis herbs, respectively. The binding energies of all compounds on COVID-19 main targets are located in the limited area of 2.22-5.30 kcal/mol. This range of binding energies can support our hypothesis for the presence of the inhibitory effects of the secondary metabolites of mentioned structures on COVID-19. Generally, among the investigated herbal structures, Cannabidiol and 7α- acetoxyroyleanone compounds with the highest binding energy have the most inhibitory potential. The least inhibitory effects are related to the Curzerene and Incensole structures by the lowest binding affinity.

Conclusion: The general arrangement of the basis of the potential barrier of binding energies is in the order below: Cannabidiol > 7α-acetoxyroyleanone > Harmaline> Incensole > Curzerene. Finally, the range of docking scores for investigated herbal compounds on the mentioned targets indicates that the probably inhibitory effects on these targets obey the following order: main protease> RNA-dependent RNA polymerase> PLpro> NSP15> spike glycoprotein.

Keywords: COVID-19, inhibitory effects, molecular docking, secondary metabolites, treatment, medicinal plants.

Graphical Abstract
Aronson JK. Coronaviruses–a general introduction 2020. Available From:
Park WB, Kwon NJ, Choi SJ, et al. Virus isolation from the first patient with SARS-CoV-2 in Korea. J Korean Med Sci 2020; 35(7): e84.
[] [PMID: 32080990]
Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. Pediatr Infect Dis J 2005; 24(11) (Suppl.): S223-7.
[] [PMID: 16378050]
Zare Gheshlaghi S, Nakhaei E, Ebrahimi A, et al. Analysis of medicinal and therapeutic potential of Withania somnifera derivatives against COVID-19. J Biomol Struct Dyn 2023; 41(14): 6883-93.
[] [PMID: 35993530]
Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181(4): 905-13.
Mostafa-Hedeab G. ACE2 as drug target of COVID-19 virus treatment, simplified updated review. Rep Biochem Mol Biol 2020; 9(1): 97-105.
[] [PMID: 32821757]
Kalidindi SR. Protection against CORONAVIRUS infection by extracts and extract components. US20220054575A1, 2022.
Su Y-C, Chiou W-H, Kuo Y-H, et al. Composition of plant ingredients, herbal composition and preparation method of the herbal composition. US20210353703A1, 2021.
Zhong S, Yu H. Miller Extracts of Scutellaria for the Treatment of SARS. US20080038382A1, 2008.
Jasim NA-GNA, Ahmed NZ. Immunomodulatory composition to treat and prevent COVID-19 illness. US011260097B2, 2022.
Reiss CS. Cannabinoids, and viral infections. Pharmaceuticals (Basel) 2010; 3(6): 1873-86.
[] [PMID: 20634917]
Al-Yasiry ARM, Kiczorowska B. Frankincense-therapeutic properties. Advances in Hygiene & Experimental Medicine 2016; 70: 380-9.
Byler K, Setzer W. Protein targets of Frankincense: A reverse docking analysis of terpenoids from Boswellia oleo-gum resins. Medicines (Basel) 2018; 5(3): 96.
[] [PMID: 30200355]
Govindarajan M, Rajeswary M, Senthilmurugan S, et al. Curzerene, trans-β-elemenone, and γ-elemene as effective larvicides against Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus: Toxicity on non-target aquatic predators. Environ Sci Pollut Res Int 2018; 25(11): 10272-82.
[] [PMID: 28353108]
Moradi M-T, Karimi A, Fotouhi F, Kheiri S, Torabi A. In vitro and in vivo effects of Peganum harmala L. seeds extract against influenza A virus. Avicenna J Phytomed 2017; 7(6): 519-30.
[PMID: 29299435]
Tajuddeen N, Van Heerden FR. Antiplasmodial natural products: An update. Malar J 2019; 18(1): 404.
[] [PMID: 31805944]
Fronza M. Phytochemical investigation of the roots of Peltodon longipes and in vitro cytotoxic studies of abietane diterpenes 2011.
Jassbi AR, Eghtesadi F, Hazeri N, et al. The roots of Salvia rhytidea: A rich source of biologically active diterpenoids. Nat Prod Res 2017; 31(4): 477-81.
[] [PMID: 27266560]
Eghtesadi F, Moridi Farimani M, Hazeri N, Valizadeh J. Abietane and nor-abitane diterpenoids from the roots of Salvia rhytidea. Springerplus 2016; 5(1): 1068.
[] [PMID: 27462516]
da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. Essential oils as antiviral agents, the potential of essential oils to treat SARS-CoV-2 infection: An in-silico investigation. Int J Mol Sci 2020; 21(10): 3426.
[] [PMID: 32408699]
Alyafei N. Can Myrrh Combat COVID-19? Iberoam J Med 2020; 2(3): 223-9.
Perez RM. Antiviral activity of compounds isolated from plants. Pharm Biol 2003; 41(2): 107-57.
Costiniuk CT, Saneei Z, Routy JP, et al. Oral cannabinoids in people living with HIV on effective antiretroviral therapy: CTN PT028—study protocol for a pilot randomised trial to assess safety, tolerability and effect on immune activation. BMJ Open 2019; 9(1): e024793.
[] [PMID: 30659041]
Florian M-LE, Kronkright DP, Norton RE. The conservation of artifacts made from plant materials. Los Angeles, California: Getty Publications 1991.
Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 2020; 16(1): 9-29.
[] [PMID: 31831863]
Barlow A, Landolf KM, Barlow B, et al. Review of emerging pharmacotherapy for the Treatment of coronavirus disease 2019. Pharmacotherapy 2020; 40(5): 416-37.
[] [PMID: 32259313]
Kim Y, Jedrzejczak R, Maltseva NI, et al. Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2. Protein Sci 2020; 29(7): 1596-605.
[] [PMID: 32304108]
Choudhary MI, Shaikh M. tul-Wahab A, ur-Rahman A. in silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation. PLoS One 2020; 15(7): e0235030.
[] [PMID: 32706783]
Karpiński TM, Kwaśniewski M, Ożarowski M, Alam R. In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro). Herba Pol 2021; 67(2): 1-8.
Kim S, Thiessen PA, Bolton EE, et al. PubChem substance and compound databases. Nucleic Acids Res 2016; 44(D1): D1202-13.
[] [PMID: 26400175]
Lengauer T, Rarey M. Computational methods for biomolecular docking. Curr Opin Struct Biol 1996; 6(3): 402-6.
[] [PMID: 8804827]
Zhao H, Caflisch A. Discovery of ZAP70 inhibitors by high-throughput docking into a conformation of its kinase domain generated by molecular dynamics. Bioorg Med Chem Lett 2013; 23(20): 5721-6.
[] [PMID: 23993776]
Chan JFW, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020; 395(10223): 514-23.
[] [PMID: 31986261]
Hilgenfeld R. From SARS to MERS: Crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J 2014; 281(18): 4085-96.
[] [PMID: 25039866]
Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237-61.
[] [PMID: 27578435]
Ghosh AK, Takayama J, Rao KV, et al. Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: Design, synthesis, protein-ligand X-ray structure and biological evaluation. J Med Chem 2010; 53(13): 4968-79.
[] [PMID: 20527968]
Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics 2020; 47(2): 119-21.
[] [PMID: 32173287]
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3): 269-71.
[] [PMID: 32020029]
Han DP, Lohani M, Cho MW. Specific asparagine-linked glycosylation sites are critical for DC-SIGN- and L-SIGN-mediated severe acute respiratory syndrome coronavirus entry. J Virol 2007; 81(21): 12029-39.
[] [PMID: 17715238]
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]
Wu K, Li W, Peng G, Li F. Crystal structure of NL63 respiratory coronavirus receptor-binding domain complexed with its human receptor. Proc Natl Acad Sci USA 2009; 106(47): 19970-4.
[] [PMID: 19901337]
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 94(7): e00127-20.
[] [PMID: 31996437]
Jin Z, Du X, Xu Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582(7811): 289-93.
[] [PMID: 32272481]
Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020; 368(6489): 409-12.
[] [PMID: 32198291]
Subissi L, Posthuma CC, Collet A, et al. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci USA 2014; 111(37): E3900-9.
[] [PMID: 25197083]
Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382(10): 929-36.
Doublié S, Ellenberger T. The mechanism of action of T7 DNA polymerase. Curr Opin Struct Biol 1998; 8(6): 704-12.
[] [PMID: 9914251]
Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci 2020; 248: 117477.
[] [PMID: 32119961]
Elfiky AA, Ismail AM. Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures. SAR QSAR Environ Res 2018; 29(5): 409-18.
[] [PMID: 29652194]
Yuan L, Chen Z, Song S, et al. p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling. J Biol Chem 2015; 290(5): 3172-82.
[] [PMID: 25505178]
Harcourt BH, Jukneliene D, Kanjanahaluethai A, et al. Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity. J Virol 2004; 78(24): 13600-12.
[] [PMID: 15564471]
Amin SA, Ghosh K, Gayen S, Jha T. Chemical-informatics approach to COVID-19 drug discovery: Monte Carlo based QSAR, virtual screening and molecular docking study of some in-house molecules as papain-like protease (PLpro) inhibitors. J Biomol Struct Dyn 2021; 39(13): 4764-73.
[] [PMID: 32568618]
Ye Y, Scheel H, Hofmann K, Komander D. Dissection of USP catalytic domains reveals five common insertion points. Mol Biosyst 2009; 5(12): 1797-808.
[] [PMID: 19734957]
Báez-Santos YM, St John SE, Mesecar AD. The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds. Antiviral Res 2015; 115: 21-38.
[] [PMID: 25554382]
Deng X, Baker SC. An “Old” protein with a new story: Coronavirus endoribonuclease is important for evading host antiviral defenses. Virology 2018; 517: 157-63.
[] [PMID: 29307596]
Zhang L, Li L, Yan L, et al. Structural and biochemical characterization of endoribonuclease Nsp15 encoded by Middle East respiratory syndrome coronavirus. J Virol 2018; 92(22): e00893-18.
[] [PMID: 30135128]
Bhardwaj K, Palaninathan S, Alcantara JMO, et al. Structural and functional analyses of the severe acute respiratory syndrome coronavirus endoribonuclease Nsp15. J Biol Chem 2008; 283(6): 3655-64.
[] [PMID: 18045871]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy