Mushroom-derived bioactive compounds potentially serve as the inhibitors of SARS-CoV-2 main protease: An in silico approach

10.1016/j.jtcme.2020.12.002

Panthakarn Rangsinth；Chanin Sillapachaiyaporn；Sunita Nilkhet；Tewin Tencomnao；Alison T. Ung；Siriporn Chuchawankul

COVID-19 ； Anti-HIV protease ； Anti-SARS-CoV-2 main protease ； Mushrooms ； Molecular docking ； ADMET analysis

Journal of Traditional and Complementary Medicine

11卷2期（2021 / 03 / 01）

158 - 172

英文

Background and aim: Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become the world pandemic. There is a race to develop suitable drugs and vaccines for the disease. The anti-HIV protease drugs are currently repurposed for the potential treatment of COVID-19. The drugs were primarily screened against the SARS-CoV-2 main protease. With an urgent need for safe and effective drugs to treat the virus, we have explored natural products isolated from edible and medicinal mushrooms that have been reported to possess anti-HIV protease. Experimental procedures: We have examined 36 compounds for their potential to be SARS-CoV-2 main protease inhibitors using molecular docking study. Moreover, drug-likeness properties including absorption, distribution, metabolism, excretion and toxicity were evaluated by in silico ADMET analysis. Results: Our AutoDock study showed that 25 of 36 candidate compounds have the potential to inhibit the main viral protease based on their binding affinity against the enzyme's active site when compared to the standard drugs. Interestingly, ADMET analysis and toxicity prediction revealed that 6 out of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F and velutin. Conclusion: Our study highlights the potential of existing mushroom-derived natural compounds for further investigation and possibly can be used to fight against SARS-CoV-2 infection. Taxonomy (classification by evise): Disease, Infectious Disease, Respiratory System Disease, Covid-19, Traditional Medicine, Traditional Herbal Medicine, Phamaceutical Analysis.

1. Prasansuklab, A,Theerasri, A,Rangsinth, P,Sillapachaiyaporn, C,Chuchawankul, S,Tencomnao, T(2020).Anti-COVID-19 drug candidates: a review on potential biological activities of natural products in the management of new coronavirus infection.J Tradit Complement Med
   連結：
2. Sillapachaiyaporn, C,Chuchawankul, S.(2019).HIV-1 protease and reverse transcriptase inhibition by tiger milk mushroom (Lignosus rhinocerus) sclerotium extracts: in vitro and in silico studies.J Tradit Complement Med,10(4),396-404.
   連結：
3. Akbar, R,Yam, WK(2011).Interaction of ganoderic acid on HIV related target: mo-lecular docking studies.Bioinformation,7(8),413-417.
4. Anand, K,Ziebuhr, J,Wadhwani, P,Mesters, JR,Hilgenfeld, R(2003).Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs.Science.,300(5626),1763-1767.
5. Arabi, YM,Alothman, A,Balkhy, HH(2018).Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-b1b (MIRACLE trial): study protocol for a randomized controlled trial.Trials,19(1),81.
6. Benarba, B,Pandiella, A.(2020).Medicinal plants as sources of active molecules against COVID-1911.Front Pharmacol,1-16.
7. Benigni, R,Bossa, C,Jeliazkova, N,Netzeva, T,Worth, A(2008).The Benigni/Bossa rulebase for mutagenicity and carcinogenicity - a module of Toxtree.JRC Scientific and Technical Reports,1-78.
8. Benigni, R,Bossa, C,Netzeva, T,Rodomonte, A,Tsakovska, I(2007).Mechanistic QSAR of aromatic amines: new models for discriminating between homocyclic mutagens and nonmutagens, and validation of models for carcinogens.Environ Mol Mutagen,48(9),754-771.
9. Bhardwaj, V,Singh, R,Singh, P,Purohit, R,Kumar, S(2020).Elimination of bitter-off taste of stevioside through structure modification and computational interventions.J Theor Biol,486,110094.
10. Bhardwaj, VK,Purohit, R(2020).Targeting the protein-protein interface pocket of Aurora-A-TPX2 complex: rational drug design and validation.J Biomol Struct Dyn,1-10.
11. Bhardwaj, VK,Singh, R,Sharma, J,Das, P,Purohit, R(2020).Structural based study to identify new potential inhibitors for dual specificity tyrosine-phosphorylation-regulated kinase.Comput Methods Progr Biomed,194,105494.
12. Bhardwaj, VK,Singh, R,Sharma, J,Rajendran, V,Purohit, R,Kumar, S(2020).Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors.J Biomol Struct Dyn,1-10.
13. Bhuiyan, FR,Howlader, S,Raihan, T,Hasan, M(2020).Plants metabolites: possibility of natural therapeutics against the COVID-19 pandemic7.Front Med,1-26.
14. Cao, B,Wang, Y,Wen, D(2020).A trial of lopinavir-ritonavirses in adults hospitalized with severe COVID-19.N Engl J Med.,382(19),1787-1799.
15. Chen, N,Zhou, M,Dong, X(2020).Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet,395(10223),507-513.
16. Chu, CM,Cheng, VC,Hung, IF(2004).Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.Thorax,59(3),252-256.
17. Cui, J,Li, F,Shi, ZL(2019).Origin and evolution of pathogenic coronaviruses.Nat Rev Microbiol,17(3),181-192.
18. Dai, W,Zhang, B,Su, H(2020).Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.Science,368(6497),1331-1335.
19. Daina, A,Michielin, O,Zoete, V(2017).SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.Sci Rep,7,42717.
20. El Dine, RS,El Halawany, AM,Ma, C-M,Hattori, M(2009).Inhibition of the dimerization and active site of HIV-1 protease by secondary metabolites from the Vietnamese mushroom Ganoderma colossum.J Nat Prod,72(11),2019-2023.
21. El Dine, RS,El Halawany, AM,Ma, C-M,Hattori, M(2008).Anti-HIV-1 protease activity of lanostane triterpenes from the Vietnamese mushroom Ganoderma colossum.J Nat Prod,71(6),1022-1026.
22. el-Mekkawy, S,Meselhy, MR,Nakamura, N(1998).Anti-HIV-1 and anti-HIV-1-protease substances from Ganoderma lucidum.Phytochemistry,49(6),1651-1657.
23. Elsayed, EA,El Enshasy, H,Wadaan, MA,Aziz, R(2014).Mushrooms: a potential natural source of anti-inflammatory compounds for medical applications.Mediat Inflamm,2014,805841.
24. Enmozhi, SK,Raja, K,Sebastine, I,Joseph, J(2020).Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach.J Biomol Struct Dynam,1-7.
25. Fredenhagen, A,Petersen, F,Tintelnot-Blomley, M,Rösel, J,Mett, H,Hug, P(1997).Semicochliodinol A and B: inhibitors of HIV-1 protease and EGF-R protein tyrosine kinase related to asterriquinones produced by the fungus Chrysosporium merdarium.J Antibiot,50(5),395-401.
26. Fuzimoto, AD,Isidoro, C(2020).The antiviral and coronavirus-host protein pathways inhibiting properties of herbs and natural compounds - additional weapons in the fight against the COVID-19 pandemic?.J Tradit, Complementary Med,10(4),405-419.
27. Gaur, T,Rao, PB(2017).Analysis of antibacterial activity and bioactive compounds of the giant mushroom, Macrocybe gigantea (agaricomycetes), from India.Int J Med Mushrooms,19(12),1083-1092.
28. Gibbs JW. A Method of Geometrical Representation of the Thermodynamic Properties by Means of Surfaces. Transactions of the Connecticut Academy of Arts and Sciences2. New Haven; 1873:382-404.
29. Gogoi, N,Chowdhury, P,Goswami, AK,Das, A,Chetia, D,Gogoi, B(2020).Computational guided identification of a citrus flavonoid as potential inhibitor of SARS-CoV-2 main protease.Mol Divers,1-15.
30. Gyebi, GA,Ogunro, OB,Adegunloye, AP,Ogunyemi, OM,Afolabi, SO(2020).Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CL(pro)): an in silico screening of alkaloids and terpenoids from African medicinal plants.J Biomol Struct Dynam,1-13.
31. Habibi, E,Sadat-Ebrahimi, SE,Mousazadeh, SA,Amanzadeh, Y(2015).Mycochemical investigation of the Turkey tail medicinal mushroom Trametes versicolor (higher basidiomycetes): a potential application of the isolated compounds in documented pharmacological studies.Int J Med Mushrooms,17(3),255-265.
32. Hu, Q,Yuan, B,Xiao, H(2018).Polyphenols-rich extract from Pleurotus eryngii with growth inhibitory of HCT116 colon cancer cells and anti-inflammatory function in RAW264.7 cells.Food & function,9(3),1601-1611.
33. Islam, R,Parves, MR,Paul, AS(2020).A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2.J Biomol Struct Dynam,1-12.
34. Jin, Z,Du, X,Xu, Y(2020).Structure of M(pro) from COVID-19 virus and discovery of its inhibitors.Nature,582,289-293.
35. Jin, Z,Zhao, Y,Sun, Y(2020).Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur.Nat Struct Mol Biol,27,529-532.
36. Kalogeropoulos, N,Yanni, AE,Koutrotsios, G,Aloupi, M(2013).Bioactive micro-constituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece.Food Chem Toxicol : Int J Publ Br Ind Biol Res Assoc,55,378-385.
37. Karaman, M,Jovin, E,Malbasa, R,Matavuly, M,Popovic, M(2010).Medicinal and edible lignicolous fungi as natural sources of antioxidative and antibacterial agents.Phytother Res : PTR,24(10),1473-1481.
38. Kashiwada, Y,Hashimoto, F,Cosentino, LM,Chen, CH,Garrett, PE,Lee, KH(1996).Betu-linic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents.J Med Chem,39(5),1016-1017.
39. Khaerunnisa, S,Kurniawan, H,Awaluddin, R,Suhartati, S,Soetjipto, S(2020).Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study1.Preprints,1-14.
40. Kim, JY,Choe, PG,Oh, Y(2020).The first case of 2019 novel coronavirus pneumonia imported into Korea from Wuhan, China: implication for infection prevention and control measures.J Kor Med Sci.,35(5),e61.
41. Kumar, A,Choudhir, G,Shukla, SK(2020).Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches.J Biomol Struct Dynam,1-21.
42. Kumar, A,Choudhir, G,Shukla, SK(2020).Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches.J Biomol Struct Dyn,1-11.
43. Kumar, V,Shin, JS,Shie, JJ(2017).Identification and evaluation of potent Middle East respiratory syndrome coronavirus (MERS-CoV) 3CL(Pro) inhibitors.Antivir Res,141,101-106.
44. Kumar, V,Tan, KP,Wang, YM,Lin, SW,Liang, PH(2016).Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors.Bioorg Med Chem,24(13),3035-3042.
45. Lee, YS,Kang, YH,Jung, JY(2008).Inhibitory constituents of aldose reductase in the fruiting body of Phellinus linteus.Biol Pharm Bull,31(4),765-768.
46. Linnakoski, R,Reshamwala, D,Veteli, P,Cortina-Escribano, M,Vanhanen, H,Marjomäki, V(2018).Antiviral agents from fungi: diversity, mechanisms and potential applications.Front Microbiol,9,2325.
47. Lipinski, CA,Lombardo, F,Dominy, BW,Feeney, PJ(2001).Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv Drug Deliv Rev,46(1-3),3-26.
48. Liu, C,Zhao, S,Zhu, C(2020).Ergosterol ameliorates renal inflammatory responses in mice model of diabetic nephropathy.Biomedicine & pharmacotherapy,128,110252.
49. Liu, J,Jia, L,Kan, J,Jin, CH(2013).In vitro and in vivo antioxidant activity of ethanolic extract of white button mushroom (Agaricus bisporus).Food Chem Toxicol : Int J Publ Br Ind Biol Res Assoc,51,310-316.
50. Ma, C,Nakamura, N,Miyashiro, H,Hattori, M,Shimotohno, K(1999).Inhibitory effects of constituents from Cynomorium songaricum and related triterpene derivatives on HIV-1 protease.Chem Pharm Bull,47(2),141-145.
51. Mengoni, F,Lichtner, M,Battinelli, L(2002).In vitro anti-HIV activity of oleanolic acid on infected human mononuclear cells.Planta Med,68(2),111-114.
52. Min, BS,Nakamura, N,Miyashiro, H,Bae, KW,Hattori, M(1998).Triterpenes from the spores of Ganoderma lucidum and their inhibitory activity against HIV-1 protease.Chem Pharm Bull,46(10),1607-1612.
53. Modi, M,Goel, T,Das, T(2013).Ellagic acid & gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activity.Indian J Med Res.,137(3),540-548.
54. Muszyńska, B,Grzywacz-Kisielewska, A,Kała, K,Gdula-Argasińska, J(2018).Anti-in-flammatory properties of edible mushrooms: a review.Food Chem,243,373-381.
55. Nallathamby, N,Phan, CW,Seow, SL(2017).A status review of the bioactive activities of tiger milk mushroom Lignosus rhinocerotis (cooke) Ryvarden.Front Pharmacol,8,998.
56. Nasution, MAF,Toepak, EP,Alkaff, AH,Tambunan, USF(2018).Flexible docking-based molecular dynamics simulation of natural product compounds and Ebola virus Nucleocapsid (EBOV NP): a computational approach to discover new drug for combating Ebola.BMC Bioinf,19(Suppl 14),419.
57. Ngai, PH,Zhao, Z,Ng, TB(2005).Agrocybin, an antifungal peptide from the edible mushroom Agrocybe cylindracea.Peptides,26(2),191-196.
58. Nutho, B,Mahalapbutr, P,Hengphasatporn, K(2020).Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms.Biochemistry,59(18),1769-1779.
59. Pillaiyar, T,Manickam, M,Namasivayam, V,Hayashi, Y.,Jung, S-HJ(2016).An overview of severe acute respiratory syndromeecoronavirus (SARS-CoV) 3CL protease inhibitors.J Med Chem,59(14),6595-6628.
60. Pires, DEV,Blundell, TL,Ascher, DB(2015).pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures.J Med Chem,58(9),4066-4072.
61. Qiu, H,Wu, J,Hong, L,Luo, Y,Song, Q,Chen, D(2020).Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study.The Lancet Infectious disea,20(6),689-696.
62. Rahman, MA,Abdullah, N,Aminudin, N(2015).Antioxidative effects and inhibition of human low density lipoprotein oxidation in vitro of polyphenolic compounds in Flammulina velutipes (golden needle mushroom).Oxidative Medicine and Cellular Longevity,2015,1-10.
63. Rahman, MA,Abdullah, N,Aminudin, N(2018).Lentinula edodes (shiitake mushroom): an assessment of in vitro anti-atherosclerotic bio-functionality.Saudi J Biol Sci.,25(8),1515-1523.
64. Rajagopal, K,Varakumar, P,Baliwada, A,Byran, G(2020).Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach.Future J Pharmaceut Sci,6(1),104.
65. Sato, N,Zhang, Q,Ma, C-M,Hattori, M(2009).Anti-human immunodeficiency virus-1 protease activity of new lanostane-type triterpenoids from Ganoderma sinense.Chem Pharm Bull,57(10),1076-1080.
66. Serafin, MB,Bottega, A,Foletto, VS,da Rosa, TF,Hörner, A,Hörner, R(2020).Drug repositioning is an alternative for the treatment of coronavirus COVID-19.Int J Antimicrob Agents,105969.
67. Sevindik, M,Rasul, A,Hussain, G(2018).Determination of anti-oxidative, anti-microbial activity and heavy metal contents of Leucoagaricus leucothites.Pak J Pharm Sci,31(5),2163-2168.
68. Sharma, J,Bhardwaj, VK,Das, P,Purohit, R(2020).Identification of naturally originated molecules as g-aminobutyric acid receptor antagonist.J Biomol Struct Dyn,1-12.
69. Sheahan, TP,Sims, AC,Leist, SR(2020).Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV.Nat Commun,11(1),222.
70. Sillapachaiyaporn, C,Nilkhet, S,Ung, AT,Chuchawankul, S(2019).Anti-HIV-1 protease activity of the crude extracts and isolated compounds from Auricularia poly-tricha.BMC Compl Alternative Med,19(1),351.
71. Singh, R,Bhardwaj, V,Das, P,Purohit, R(2020).Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective.J Biomol Struct Dynam,38(17),5126-5135.
72. Sun, X,Feng, X,Zheng, D(2019).Ergosterol attenuates cigarette smoke extract-induced COPD by modulating inflammation, oxidative stress and apoptosis in vitro and in vivo.Clinical science,133(13),1523-1536.
73. Suwannarach, N,Kumla, J,Sujarit, K,Pattananandecha, T,Saenjum, C,Lumyong, S(2020).Natural bioactive compounds from fungi as potential candidates for protease inhibitors and immunomodulators to apply for coronaviruses.Molecules,25(8)
74. Tong, S,Zhong, H,Yi, C(2014).Simultaneous HPLC determination of ergosterol and 22,23-dihydroergosterol in Flammulina velutipes sterol-loaded microemulsion.Biomed Chromatogr : BMC (Biomed Chromatogr),28(2),247-254.
75. Tsuji, M(2020).Potential anti-SARS-CoV-2 drug candidates identified through virtual screening of the ChEMBL database for compounds that target the main coro-navirus protease.FEBS open bio,10(6),995-1004.
76. Tu, YF,Chien, CS,Yarmishyn, AA(2020).A review of SARS-CoV-2 and the ongoing clinical trials.Int J Mol Sci.,21(7)
77. Uniyal, A,Mahapatra, MK,Tiwari, V,Sandhir, R,Kumar, R(2020).Targeting SARS-CoV-2 main protease: structure based virtual screening, in silico ADMET studies and molecular dynamics simulation for identification of potential inhibitors.J Biomol Struct Dynam,1-17.
78. Wang, CR,Zhou, R,Ng, TB,Wong, JH,Qiao, WT,Liu, F(2014).First report on isolation of methyl gallate with antioxidant, anti-HIV-1 and HIV-1 enzyme inhibitory activities from a mushroom (Pholiota adiposa).Environ Toxicol Pharmacol,37(2),626-637.
79. Wang, D,Hu, B,Hu, C(2020).Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, China.Jama,323(11),1061-1069.
80. Wang, H,Ng, TB(2001).Isolation and characterization of velutin, a novel low-molecular-weight ribosome-inactivating protein from winter mushroom (Flammulina velutipes) fruiting bodies.Life Sci,68(18),2151-2158.
81. World Health Organization. Coronavirus disease (COVID-19) Situation Report. World Health Organization; 27 December 2020.
82. Yang, H,Xie, W,Xue, X(2005).Design of wide-spectrum inhibitors targeting coronavirus main proteases.PLoS Biol,3(10),e324.
83. Ye, XT,Luo, YL,Xia, SC(2020).Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019.Eur Rev Med Pharmacol Sci.,24(6),3390-3396.
84. Yoon, KN,Alam, N,Lee, KR(2011).Antioxidant and antityrosinase activities of various extracts from the fruiting bodies of Lentinus lepideus.Molecules,16(3),2334-2347.
85. Zhang, CC,Yin, X,Cao, CY,Wei, J,Zhang, Q,Gao, JM(2015).Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells.Bioorg Med Chem Lett,25(22),5078-5082.
86. Zhu, N,Zhang, D,Wang, W(2020).A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med.,382(8),727-733.
87. Zumla, A,Chan, JF,Azhar, EI,Hui, DS,Yuen, KY(2016).Coronaviruses - drug discovery and therapeutic options.Nat Rev Drug Discov.,15(5),327-347.

1. Lee-Yan Sheen,Ciro Isidoro,Ashley Chiung-Fang Chang(2022).Natural products as a source of novel drugs for treating SARS-CoV2 infection.Journal of Traditional and Complementary Medicine,12(1),1-5.
2. Sameh S. Elhady,Khaled M. Darwish,Ahmed Ashour,Ahmed A. Zaki,Ahmed A. Al-Karmalawy(2022).Calendulaglycoside A showing potential activity against SARS-CoV-2 main protease: Molecular docking, molecular dynamics, and SAR studies.Journal of Traditional and Complementary Medicine,12(1),16-34.
3. Vijay Kumar Bhardwaj,Sanjay Kumar,Rituraj Purohit,Rahul Singh,Jatin Sharma(2022).In-silico evaluation of bioactive compounds from tea as potential SARS-CoV-2 nonstructural protein 16 inhibitors.Journal of Traditional and Complementary Medicine,12(1),35-43.