Computer-aided Drug Design Targeting at Nonstructural Protein of Influenza A Virus
|School||Chinese Academy of Agricultural Sciences|
|Course||Preventive Veterinary Medicine|
|Keywords||Influenza A virus NS1 inhibitors Mode of action Virtual Screening|
Major pathogen of influenza A virus is not only a seasonal flu, and the history of several influenza pandemic caused by influenza A virus. 2009 outbreak of the H1N1 subtype of influenza pandemic is still worldwide continued potential influenza pandemic pathogens, such as H5N1, H9N2 infection cases are also daily increased worldwide influenza prevention and control situation very serious. Although the vaccine is the most effective measures to prevent and control influenza, but for emerging, the antigenicity of the virus to mutate caused by influenza, medication to alleviate pain, reduce mortality is of great significance. At present, the research and development of new anti-influenza virus type A drug has become a consensus. NS1 protein of influenza A virus replication process can enhance the virulence of the virus, the resistance to the antiviral immune response of the host cell, is a potential target for anti-influenza drug action. Combined research NS1 structure characteristics and possible drug targets, homology modeling method to establish the strains HK, PR, Tx, WSN, GD NS1 protein RNA-binding domain dimer structure model, full-length monomer the structural model, full-length dimeric structure model, and use of PROCHECK assess the quality of the model, using bioinformatics methods based on analysis of the the NS1 potential functional sites. The results show that the model structure is reasonable, and can be used for functional studies and drug screening, and identified the NS1 potential drug targets 4, respectively, defined as site1, site3, site5 and site6. Using the established structure of the model and known the NS1 protein inhibitors NSC109834, NSC128164 NSC125044 NSC95676 molecular docking analysis of these compounds and NS1 role of targets and modes of action. The analysis results show which NSC109834 NSC128164 NSC125044 simultaneously acting on site1 site3 two targets, while NSC95676 only active in site1. Inhibitors mechanism by preventing the NS1 and of dsRNA to inhibit the function of NS1, CPSF30 the binding; but different from the four kinds of the binding mode of inhibitors in site1 loci, NSC109834, NSC128164, NSC125044 having steric hindrance, repulsion prevents static electricity The combination of dsRNA and the NS1 protein, while the minimum NSC95676 affinity molecule whole showed electropositive, through steric exclusion the Arg38 affect the binding of RNA. Identified NS1 RNA binding pocket (site1) as a target, druglike ZINC8.0 database, 1,140,000 small molecules leadlike sub-library for the the screening object, the establishment of a virtual screening of inhibitors NS1. After two rounds of screening (initial screening and fine butt) identified the the eight possible lead compounds: ZINC00197916, ZINC01723322 ZINC02827168 ZINC04103765, ZINC05065460, ZINC06721146, ZINC13151400, ZINC08012842. Structural group characteristic of these compounds is similar to the known inhibitors, and both ends of the majority of molecules having a hydrophobic center connection of the intermediate carbon chain skeleton. Found after a preliminary analysis of its binding mode the lead compound NS1 protein has a strong affinity to the formation of hydrogen bonds and interaction, ZINC02827168 play the activity mechanism with NSC95676 similar, while the other seven compounds play activity mechanism NSC109834 NSC128164 , NSC125044 same. The NS1 protein potential drug targets identified in this study, the lead compound known inhibitor binding mode and screened NS1 may lay the foundation for the novel NS1 inhibitors.