title: Inhibition of histo-blood group antigen binding as a novel strategy to block norovirus infections.
abstract: 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 of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC50<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC50<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design.
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Xu-Fu
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Monica
authors.initials: M
authors.lastname: Chhabra
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Dai
authors.forename: Jarek
authors.initials: J
authors.lastname: Meller
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D001789:Blood Group Antigens / Q000737:chemistry / Q000378:metabolism*; D017250:Caliciviridae Infections / Q000188:drug therapy / Q000378:metabolism*; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D005759:Gastroenteritis / Q000188:drug therapy / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D029322:Norovirus / Q000378:metabolism*; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D055503:Protein Multimerization; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D000998:Antiviral Agents; D001789:Blood Group Antigens; D036022:Capsid Proteins; D009844:Oligosaccharides; D054852:Small Molecule Libraries
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