Generic placeholder image

Combinatorial Chemistry & High Throughput Screening


ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Theoretical Study of the Molecular Mechanism of Maxingyigan Decoction Against COVID-19: Network Pharmacology-based Strategy

Author(s): Mingzhu Wang, Deyu Fu*, Lei Yao and Jianhua Li

Volume 24, Issue 2, 2021

Published on: 06 August, 2020

Page: [294 - 305] Pages: 12

DOI: 10.2174/1386207323666200806164635

Price: $65


Aim and Objective: Maxingyigan (MXYG) decoction is a traditional Chinese medicine (TCM) prescription. However, how MXYG acts against coronavirus disease 2019 (COVID-19) is not known. We investigated the active ingredients and the therapeutic targets of MXYG decoction against COVID-19.

Methods: A network pharmacology strategy involving drug-likeness evaluation, prediction of oral bioavailability, network analyses, and virtual molecular docking was used to predict the mechanism of action of MXYG against COVID-19.

Results: Thirty-three core COVID-19-related targets were identified from 1023 gene targets through analyses of protein–protein interactions. Eighty-six active ingredients of MXYG decoction hit by 19 therapeutic targets were screened out by analyses of a compound–compound target network. Via network topology, three “hub” gene targets (interleukin (IL-6), caspase-3, IL-4) and three key components (quercetin, formononetin, luteolin) were recognized and verified by molecular docking. Compared with control compounds (ribavirin, arbidol), the docking score of quercetin to the IL-6 receptor was highest, with a score of 5. Furthermore, the scores of three key components to SARS-CoV-2 are large as 4, 5, and 5, respectively, which are even better than those of ribavirin at 3. Bioinformatics analyses revealed that MXYG could prevent and treat COVID-19 through anti-inflammatory and immunity-based actions involving activation of T cells, lymphocytes, and leukocytes, as well as cytokine–cytokine-receptor interaction, and chemokine signaling pathways.

Conclusion: The hub genes of COVID-19 helped to reveal the underlying pathogenesis and therapeutic targets of COVID-19. This study represents the first report on the molecular mechanism of MXYG decoction against COVID-19.

Keywords: TCM formulations, novel coronavirus, COVID-19, network pharmacology, molecular docking, molecular mechanism.

Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.L.; Hui, D.S.C.; Du, B.; Li, L.J.; Zeng, G.; Yuen, K.Y.; Chen, R.C.; Tang, C.L.; Wang, T.; Chen, P.Y.; Xiang, J.; Li, S.Y.; Wang, J.L.; Liang, Z.J.; Peng, Y.X.; Wei, L.; Liu, Y.; Hu, Y.H.; Peng, P.; Wang, J.M.; Liu, J.Y.; Chen, Z.; Li, G.; Zheng, Z.J.; Qiu, S.Q.; Luo, J.; Ye, C.J.; Zhu, S.Y.; Zhong, N.S. China medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med., 2020, 382(18), 1708-1720.
[] [PMID: 32109013]
Rubin, E.J.; Baden, L.R.; Morrissey, S.; Campion, E.W. Medical Journals and the 2019-nCoV Outbreak. N. Engl. J. Med., 2020, 382(9), 866-866.
[] [PMID: 31986242]
The Lancet. Emerging understandings of 2019-nCoV. Lancet, 2020, 395(10221), 311-311.
[] [PMID: 31986259]
Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395(10223), 497-506.
[] [PMID: 31986264]
NATCM. Diagnosis and treatment protocol for coronavirus pneumonia (Trial version 7) 2020.
Xia, J. Chinese medicine masters and academicians enter the national medical treatment expert group, and Chinese medicine deeply intervenes in the whole process of new coronary pneumonia diagnosis and treatment; China Youth Daily, 2020.
Wang, Z.; Chen, X.; Lu, Y.; Chen, F.; Zhang, W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci. Trends, 2020, 14(1), 64-68.
[] [PMID: 32037389]
Ren, J.L.; Zhang, A.H.; Wang, X.J. Traditional Chinese medicine for COVID-19 treatment. Pharmacol. Res., 2020, 155104743
[] [PMID: 32145402]
Pengcao, W.; Qing, M.; Maorong, F.; Yanping, Z. Study of traditional Chinese medicine prescriptions on Treatment of cough caused by damp-heat. Chin. J. Tradit. Chin. Med. Pharm., 2010, 12(2), 1-4. [J]
Miao, Q.; Wei, P.C.; Fan, M.R.; Zhang, Y.P. Clinical study on treatment of cough variant asthma by Chinese medicine. Chin. J. Integr. Med., 2013, 19(7), 539-545.
[] [PMID: 23818206]
Deng, W.; Zhang, B. A Comprehensive Analysis of the Guidelines for Diagnosis and Treatment of Novel Coronavirus in Different Provinces in China. J. Tradit. Chin. Med., 2020, 1113(2), 1-4.
Ling, C.Q. Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-CoV-2). J. Integr. Med., 2020, 18(2), 87-88.
[] [PMID: 32122812]
Kibble, M.; Saarinen, N.; Tang, J.; Wennerberg, K.; Mäkelä, S.; Aittokallio, T. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat. Prod. Rep., 2015, 32(8), 1249-1266.
[] [PMID: 26030402]
Pei, L.; Shen, X.; Yan, Y.; Tan, C.; Qu, K.; Zou, J.; Wang, Y.; Ping, F. Virtual Screening of the multi-pathway and multi-gene regulatory molecular mechanism of Dachengqi decoction in the treatment of stroke Based on Network Pharmacology. Comb. Chem. High Throughput Screen., 2020, 23, 1-13.
[] [PMID: 32160845]
Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6, 13.
[] [PMID: 24735618]
Liu, Z.; Guo, F.; Wang, Y.; Li, C.; Zhang, X.; Li, H.; Diao, L.; Gu, J.; Wang, W.; Li, D.; He, F. BATMAN-TCM: a bioinformatics analysis tool for molecular mechanism of traditional chinese medicine. Sci. Rep., 2016, 6, 21146.
[] [PMID: 26879404]
Zhang, W.; Chen, Y.; Jiang, H.; Yang, J.; Wang, Q.; Du, Y.; Xu, H. Integrated strategy for accurately screening biomarkers based on metabolomics coupled with network pharmacology. Talanta, 2020, 211120710
[] [PMID: 32070601]
Breuza, L.; Poux, S.; Estreicher, A.; Famiglietti, M.L.; Magrane, M.; Tognolli, M.; Bridge, A.; Baratin, D.; Redaschi, N. The UniProtKB guide to the human proteome. Database, 2016, 120, 1-10.
Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, T.I.; Nudel, R.; Lieder, I.; Mazor, Y.; Kaplan, S.; Dahary, D.; Warshawsky, D.; Guan-Golan, Y.; Kohn, A.; Rappaport, N.; Safran, M.; Lancet, D. The GeneCards Suite: from gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics, 2016, 54.
Amberger, J.S.; Bocchini, C.A.; Schiettecatte, F.; Scott, A.F.; Hamosh, A. Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res., 2015, 43(Database issue), D789-D798.
[] [PMID: 25428349]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C.V. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 2019, 47(D1), D607-D613.
[] [PMID: 30476243]
Chin, C.H.; Chen, S.H.; Wu, H.H.; Ho, C.W.; Ko, M.T.; Lin, C.Y. ytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol., 2014, 8(Suppl. 4), S11.
Cattley, S.; Arthur, J.W. BioManager: the use of a bioinformatics web application as a teaching tool in undergraduate bioinformatics training. Brief. Bioinform., 2007, 8(6), 457-465.
[] [PMID: 17715151]
The Gene Ontology Consortium. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res., 2017, 45(D1), D331-D338.
[] [PMID: 27899567]
Kanehisa, M.; Furumichi, M.; Tanabe, M.; Sato, Y.; Morishima, K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res., 2017, 45(D1), D353-D361.
[] [PMID: 27899662]
Ragunathan, A.; Malathi, K.; Ramaiah, S.; Anbarasu, A. FtsA as a cidal target for Staphylococcus aureus: Molecular docking and dynamics studies. J. Cell. Biochem., 2018, 120(5), 7751-7758.
[] [PMID: 30417432]
Keskin, O.; Tuncbag, N.; Gursoy, A. Predicting protein-protein interactions from the molecular to the proteome level. Chem. Rev., 2016, 116(8), 4884-4909.
[] [PMID: 27074302]
Baruah, V.; Bose, S. Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV. J. Med. Virol., 2020, 92(5), 495-500.
[] [PMID: 32022276]
Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. HLH Across Speciality Collaboration. UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet, 2020, 395(10229), 1033-1034.
[] [PMID: 32192578]
Li, G.; Fan, Y.; Lai, Y.; Han, T.; Li, Z.; Zhou, P.; Pan, P.; Wang, W.; Hu, D.; Liu, X.; Zhang, Q.; Wu, J. Coronavirus infections and immune responses. J. Med. Virol., 2020, 92(4), 424-432.
[] [PMID: 31981224]
Okumura, A.; Pitha, P.M.; Yoshimura, A.; Harty, R.N. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J. Virol., 2010, 84(1), 27-33.
[] [PMID: 19846529]
Pauli, E.K.; Schmolke, M.; Wolff, T.; Viemann, D.; Roth, J.; Bode, J.G.; Ludwig, S. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog., 2008, 4(11)e1000196
[] [PMID: 18989459]
Zhou, Y.; Fu, B.; Zheng, X.; Wang, D.; Zhao, C.; Qi, Y.; Sun, R.; Tian, Z.; Xu, X.; Wei, H. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv, 2020.
Chen, C.; Zhang, X.R.; Ju, Z.Y.; He, W.F. Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies. Zhonghua Shao Shang Za Zhi, 2020, 36E005
Qiu, R.; Wei, X.; Zhao, M.; Zhong, C.; Zhao, C.; Hu, J.; Li, M.; Huang, Y.; Han, S.; He, T. Outcome reporting from protocols of clinical trials of Coronavirus Disease 2019 (COVID-19): a review medRxiv, 2019.
Wang, Z.F.; Wang, Y.P.; Zhang, H.M.; Fan, Y.P.; Lü, C.; Wang, Y.Y. Thinking on Clinical rational use of TCM injection in the treatment of novel coronavirus pneumonia (COVID-19). Zhonghua Yi Xue Za Zhi, 2020, 100, E016-E016.
[PMID: 32122113]
Qi, F.; Qian, S.; Zhang, S.; Zhang, Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem. Biophys. Res. Commun., 2020, 526(1), 135-140.
[] [PMID: 32199615]
Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol., 2016, 16(1), 35-50.
[] [PMID: 26711677]
Chen, T.; Liu, H.X.; Yan, H.Y.; Wu, D.M.; Ping, J. Developmental origins of inflammatory and immune diseases. Mol. Hum. Reprod., 2016, 22(8), 858-865.
[] [PMID: 27226490]
Kakizaki, M.; Watanabe, R. IL-10 expression in pyramidal neurons after neuropathogenic coronaviral infection. Neuropathology, 2017, 37(5), 398-406.
[] [PMID: 28493345]
Diemer, C.; Schneider, M.; Seebach, J.; Quaas, J.; Frösner, G.; Schätzl, H.M.; Gilch, S. Cell type-specific cleavage of nucleocapsid protein by effector caspases during SARS coronavirus infection. J. Mol. Biol., 2008, 376(1), 23-34.
[] [PMID: 18155731]
Favreau, D.J.; Meessen-Pinard, M.; Desforges, M.; Talbot, P.J. Human coronavirus-induced neuronal programmed cell death is cyclophilin d dependent and potentially caspase dispensable. J. Virol., 2012, 86(1), 81-93.
[] [PMID: 22013052]
Ren, L.; Yang, R.; Guo, L.; Qu, J.; Wang, J.; Hung, T. Apoptosis induced by the SARS-associated coronavirus in Vero cells is replication-dependent and involves caspase. DNA Cell Biol., 2005, 24(8), 496-502.
[] [PMID: 16101347]
Kindrachuk, J.; Ork, B.; Hart, B.J.; Mazur, S.; Holbrook, M.R.; Frieman, M.B.; Traynor, D.; Johnson, R.F.; Dyall, J.; Kuhn, J.H.; Olinger, G.G.; Hensley, L.E.; Jahrling, P.B. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob. Agents Chemother., 2015, 59(2), 1088-1099.
[] [PMID: 25487801]
Joshi, S.D.; Dixit, S.R.; Kirankumar, M.N.; Aminabhavi, T.M.; Raju, K.V.S.N.; Narayan, R.; Lherbet, C.; Yang, K.S. Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Eur. J. Med. Chem., 2016, 107, 133-152.
[] [PMID: 26580979]
Sama, I.E.; Ravera, A.; Santema, B.T.; van Goor, H.; Ter Maaten, J.M.; Cleland, J.G.F.; Rienstra, M.; Friedrich, A.W.; Samani, N.J.; Ng, L.L.; Dickstein, K.; Lang, C.C.; Filippatos, G.; Anker, S.D.; Ponikowski, P.; Metra, M.; van Veldhuisen, D.J.; Voors, A.A. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur. Heart J., 2020, 41(19), 1810-1817.
[] [PMID: 32388565]
Meng, J.; Xiao, G.; Zhang, J.; He, X.; Ou, M.; Bi, J.; Yang, R.; Di, W.; Wang, Z.; Li, Z.; Gao, H.; Liu, L.; Zhang, G. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg. Microbes Infect., 2020, 9(1), 757-760.
[] [PMID: 32228222]
Zakaryan, H.; Arabyan, E.; Oo, A.; Zandi, K. Flavonoids: promising natural compounds against viral infections. Arch. Virol., 2017, 162(9), 2539-2551.
[] [PMID: 28547385]
Perez-Vizcaino, F.; Fraga, C.G. Perez Vizcaino. Research trends in flavonoids and health. Arch. Biochem. Biophys., 2018, 646, 107-112.
[] [PMID: 29580946]
Chiow, K.H.; Phoon, M.C.; Putti, T.; Tan, B.K.; Chow, V.T. Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pac. J. Trop. Med., 2016, 9(1), 1-7.
[] [PMID: 26851778]
Park, H.R.; Yoon, H.; Kim, M.K.; Lee, S.D.; Chong, Y. Synthesis and antiviral evaluation of 7-O-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV). Arch. Pharm. Res., 2012, 35(1), 77-85.
[] [PMID: 22297745]
Ryu, Y.B.; Jeong, H.J.; Kim, J.H.; Kim, Y.M.; Park, J.Y.; Kim, D.; Nguyen, T.T.; Park, S.J.; Chang, J.S.; Park, K.H.; Rho, M.C.; Lee, W.S. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg. Med. Chem., 2010, 18(22), 7940-7947.
[] [PMID: 20934345]
Yao, Y.; Zhang, X.; Wang, Z.; Zheng, C.; Li, P.; Huang, C.; Tao, W.; Xiao, W.; Wang, Y.; Huang, L.; Yang, L. Deciphering the combination principles of Traditional Chinese Medicine from a systems pharmacology perspective based on Ma-huang Decoction. J. Ethnopharmacol., 2013, 150(2), 619-638.
[] [PMID: 24064232]
Kimura, M.; Kimura, I.; Guo, X.; Luo, B.; Kobayashi, S. Combined effects of Japanese-Sino medicine ‘Kakkon-to-ka-senkyu-shin’i’ and its related combinations and component drugs on adjuvant-induced inflammation in mice. Phytother. Res., 1992, 6(4), 209-216.
Jayaprakasam, B.; Yang, N.; Wen, M.C.; Wang, R.; Goldfarb, J.; Sampson, H.; Li, X.M. Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro. J. Integr. Med., 2013, 11(3), 195-205.
[] [PMID: 23743163]
Yeh, Y.A.; Herenyiova, M.; Weber, G. Quercetin: synergistic action with carboxyamidotriazole in human breast carcinoma cells. Life Sci., 1995, 57(13), 1285-1292.
[] [PMID: 7674820]
Son, H.U.; Yoon, E.K.; Yoo, C.Y.; Park, C.H.; Bae, M.A.; Kim, T.H.; Lee, C.H.; Lee, K.W.; Seo, H.; Kim, K.J.; Lee, S.H. Effects of Synergistic Inhibition on α-glucosidase by Phytoalexins in Soybeans. Biomolecules, 2019, 9(12)E828
[] [PMID: 31817312]
Das, N.; Berhow, M.A.; Angelino, D.; Jeffery, E.H. Camelina sativa defatted seed meal contains both alkyl sulfinyl glucosinolates and quercetin that synergize bioactivity. J. Agric. Food Chem., 2014, 62(33), 8385-8391.
[] [PMID: 25050614]
Pal, A.; Tripathi, A. Demonstration of bactericidal and synergistic activity of quercetin with meropenem among pathogenic carbapenem resistant Escherichia coli and Klebsiella pneumoniae. Microb. Pathog., 2020, 143104120
[] [PMID: 32169488]
Rakariyatham, K.; Wu, X.; Tang, Z.; Han, Y.; Wang, Q.; Xiao, H. Synergism between luteolin and sulforaphane in anti-inflammation. Food Funct., 2018, 9(10), 5115-5123.
[] [PMID: 30206627]
Williamson, E.M. Synergy and other interactions in phytomedicines. Phytomedicine, 2001, 8(5), 401-409.
[] [PMID: 11695885]
Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; Tian, D.S. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis., 2020, 03(13), 248.
[] [PMID: 32161940]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy