Objective:Severe cases of coronavirus disease 2019(COVID-19)are expected to have a worse prognosis than mild cases.Shenhuang Granule(SHG)has been shown to be a safe and effective treatment for severe COVID-19 in a previous randomized clinical trial,but the active chemical constituents and underlying mechanisms of action remain unknown.The goal of this study is to explore the chemical basis and mech-anisms of SHG in the treatment of severe COVID-19,using network pharmacology.Methods:Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was employed to screen chemical constituents of SHG.Putative therapeutic targets were predicted by search-ing traditional Chinese medicine system pharmacology database and analysis platform,SwissTargetPrediction,and Gene Expression Omnibus(GEO)databases.The target protein-protein inter-action network and enrichment analysis were performed to investigate the hub genes and presumptive mechanisms.Molecular docking and molecular dynamics simulations were used to verify the stability and interaction between the key chemical constituents of SHG and COVID-19 protein targets.Results:Forty-five chemical constituents of SHG were identified along with 131 corresponding therapeu-tic targets,including hub genes such as HSP90AA1,MMP9,CXCL8,PTGS2,IFNG,DNMT1,TYMS,MDM2,HDAC3 and ABCB1.Functional enrichment analysis indicated that SHG mainly acted on the neuroactive ligand-receptor interaction,calcium signaling pathway and cAMP signaling pathway.Molecular docking showed that the key constituents had a good affinity with the severe acute respiratory syndrome coron-avirus 2 protein targets.Molecular dynamics simulations indicated that ginsenoside Rg4 formed a stable protein-ligand complex with helicase.Conclusion:Multiple components of SHG regulated multiple targets to inhibit virus invasion and cytokine storm through several signaling pathways;this provides a scientific basis for clinical applications and fur-ther experiments.

Department of Emergency,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China;Acupuncture and Massage College,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Institute of Critical Care,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

[1]Xiang-ru Xu;Wen Zhang;Xin-xin Wu;Hong-qiang Yang;Yu-ting Sun;Yu-ting Pu;Bei Wang;Wei Peng;Li-hua Sun;Quan Guo;Shuang Zhou;Bang-jiang Fang-.Analysis of mechanisms of Shenhuang Granule in treating severe COVID-19 based on network pharmacology and molecular docking)[J].结合医学学报（英文版）,2022(06):561-574

Shenhuang,presumptive,Rg4

Analysis,mechanisms,Granule,treating,severe,network,pharmacology,molecular,docking,Objective,Severe,cases,coronavirus,disease,are,expected,have,worse,prognosis,than,mild,SHG,has,been,shown,safe,effective,treatment,previous,randomized,clinical,trial,but,chemical,constituents,underlying,remain,unknown,goal,this,study,explore,basis,using,Methods,Ultra,performance,liquid,chromatography,quadrupole,flight,mass,spectrometry,was,employed,screen,Putative,therapeutic,targets,were,predicted,by,search,traditional,Chinese,medicine,system,analysis,platform,SwissTargetPrediction,Gene,Expression,Omnibus,GEO,databases,protein,enrichment,performed,investigate,hub,genes,Molecular,dynamics,simulations,used,verify,stability,interaction,between,key,Results,Forty,five,identified,along,corresponding,including,such,HSP90AA1,MMP9,CXCL8,PTGS2,IFNG,DNMT1,TYMS,MDM2,HDAC3,ABCB1,Functional,indicated,that,mainly,acted,neuroactive,ligand,receptor,calcium,signaling,cAMP,showed,had,good,affinity,acute,respiratory,syndrome,ginsenoside,stable,complex,helicase,Conclusion,Multiple,components,regulated,multiple,inhibit,invasion,cytokine,storm,through,several,pathways,provides,scientific,applications,fur,experiments

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