Design,Synthesis And Biological Activity Of Neuraminidase Inhibitor Zanamivir Derivatives

Influenza is an acute viral respiratory infection caused by influenza virus.It has the characteristics of high morbidity,strong infectivity,rapid onset,rapid onset,and prone to local outbreaks,which seriously affect human health.Neuraminidase,a glycoprotein on the surface of influenza virus,plays an important role in the process of virus and microorganism invading the host.Neuraminidase inhibitor is one of the following after amantadine,rimantadine and virus vaccine.Flu-preventive and therapeutic drugs with novel mechanisms of action have broad spectrum,efficacy,low resistance,and good tolerability for each subtype influenza virus.At present,the use of neuraminidase inhibitors is an effective way to inhibit viral infection.The design and synthesis of neuraminidase inhibitors based on the structure of neuraminidase and substrates is one of the research hotspots in recent years.In order to obtain a more active,low-negative neuraminidase inhibitor compound,this article uses a computer-aided drug design approach.First,66 zanamivir analogs were collected from the latest literature to establish the best 3D-QSAR(The statistical parameters of three-dimensional quantitative structure-activity relationship?QSAR?model,CoMFA model and CoMSIA model are:q²=0.728,r²=0.988,SEE=0.146,r²pred=0.702,q²=0.750,r²=0.981,SEE=0.188,R²pred=0.702.Then,five force field patches of CoMFA and CoMSIA were analyzed and a series of novel zanamivir analogs were designed.For compounds with better predicted activity,molecular docking and molecular dynamics simulation techniques were used to further study compounds.The interactions with proteins and the mechanism of action,molecular docking results show that some key amino acid residues such as Glu119,Asp151,Arg156,Trp178,Thr225,Glu277 and Arg292 can form hydrogen bonding interactions well with ligands,20ns The results of molecular dynamics show that all the complexes are stable after 10 ns simulation time.Finally,in order to verify the readiness of theoretical studies,the newly designed compounds S1 and S2 were successfully synthesized.Their IC₅₀0 values for enzyme inhibitory activity were 35.42?m and 97.51?m,respectively,which were superior to those of zanamivir(IC₅₀=129.8?m).