Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections

摘要: Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures HBGA-binding interfaces a number representing different HBGA binding patterns opens new strategy for development antiviral compounds against through rational drug design and computer-aided virtual screening methods. In this study, docking simulations were used to identify hit targeting A B sites on surface capsid P protein GII.4 NoV (VA387). Following validation by re-docking ligands, these structural models AutoDock suite programs screen large drug-like compound library (derived from ZINC library) inhibitors blocking HBGAs. After >2 million using multistage protocol, 160 with best predicted affinities distinct chemical classes have been selected subsequent experimental validation. Twenty found be able block VA387 dimers and/or HBGAs at an IC50<40.0 µM, top 5 IC50<10.0 µM in both oligosaccharide- saliva-based assays. Interestingly, 4 top-5 shared basic structure cyclopenta [a] dimethyl phenanthren, indicating promising template further improvement design.