Study On Active Substances And Potential Multi-target Of Polyphenol Compounds For Against Influenza Virus

Influenza virus is a respiratory pathogen.Moreover,there is a strong ability of mutation and can cause periodic global pandemics.It has posed a great threat to the world economy and human health.Due to the mutability,high pathogenicity and epidemic capacity of influenza virus,it is very difficult to diagnose and prevent influenza in time.Neuraminidase inhibitors（neuraminidase inhibitors,NIs）as the currently effective anti-influenza drugs,the adverse effects and resistance are gradually increase.Therefore,it is necessary to develop novel NIs with high efficiency and low toxicity.In this paper,based on polyphenols database and leguminous Chinese medicinal materials with polyphenol,comprehensive utilization of QSAR,network pharmacology,molecular docking,dynamics simulation and in vitro assays discovers multi-target anti-influenza virus NIs and explores their inhibitory mechanism.The obtained results are as follows:（1）The constructed four QSAR models including HQSAR（2D-QSAR）and three Co MSIA（3D-QSAR）have good fitting ability and prediction ability,which provide a Quantitative prediction platform for biological activity of novel compounds.Moreover,²,² and₀²)of HQSAR model are in turn 0.959,0.836 and 0.581.² and² of three Co MSIA models are 0.902 and 0.747,0.884 and 0.557,0.897 and 0.734,respectively.₀²)of three Co MSIA models are in turn 0.812,0.886 and 0.940.（2）Based on PubChem and Phenol-Explorer database,ten polyphenols multi-target lead compounds are discovered using the constructed QSAR models,virtual screening and ADMET properties.Moreover,their docking scores are higher than that of five positive drugs（oseltamivir,peramivir,zanamivir,Ranivir and ranivir octinate）.In addition,40natural multi-target lead compounds are found through molecular docking,ADMET properties and network pharmacology from leguminous Chinese medicinal materials with polyphenol.Further experimental validation,11 compounds have the biological activity of inhibition influenza virus neuraminidase.Bioactivities of eight compounds,namely Pubchem CID 5280805（rutin）,Pubchem CID 92794（naringine-7-O-glucoside）,Pubchem CID 5318767（kaempferol-3-o-rutinside）,Pubchem CID 5281675（orientin）,Pubchem CID5481663（narcissoside）,Pubchem CID 5481224（guaijaverin）,Pubchem CID 5282102（astragalin）and Pubchem CID 3550102（schaftoside）are better than that of the positive drug oseltamivir phosphate,which have the most promising as potential multi-targets NIs drugs.（3）Inhibitory mechanisms of polyphenols compounds illustrate TLR4 and MMP9 are directly related to NEU1.Therefore,TLR4 and MMP9,HSP90AA1,TNF and MTOR are key targets of therapeutic influenza virus.the other 12 targets（NFKB1,PIK3R1,STAT1,ITGB1,CDK1,HDAC2,HSP90AA1,MAPK1,ESR1,TNF,MTOR,HIF1A）are indirectly associated with NEU1.As a results,total 14 targets are all recommended potential targets of therapeutic influenza.Therefore,the current research can be helpful in improving novel drug discovery and offer clear insights into the production of the efficient NIs drugs.