Inhibition of histo-blood group antigen binding as a novel strategy to block norovirus infections

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...

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Published in:	PloS one 2013-07, Vol.8 (7), p.e69379
Main Authors:	Zhang, Xu-Fu, Tan, Ming, Chhabra, Monica, Dai, Ying-Chun, Meller, Jarek, Jiang, Xi
Format:	Article
Language:	eng
Subjects:	Antigens Antiviral agents Antiviral Agents - chemistry Antiviral Agents - pharmacology Antiviral Agents - toxicity Binding Sites Bioinformatics Biology Blocking Blood Blood Group Antigens - chemistry Blood Group Antigens - metabolism Blood groups CAD Caliciviridae Infections - drug therapy Caliciviridae Infections - metabolism Capsid Proteins - chemistry Capsid Proteins - metabolism Chemical compounds Chemistry Computer aided design Computer Simulation Crystal structure Crystals Dimers Docking Drug development Epidemics Gastroenteritis Gastroenteritis - drug therapy Gastroenteritis - metabolism Health aspects High-Throughput Screening Assays Hospitals Humans Infectious diseases Interfaces Ligands Medical screening Medicine Molecular Docking Simulation Norovirus - metabolism Oligosaccharides - chemistry Oligosaccharides - metabolism P protein Pediatrics Protein Binding - drug effects Protein Conformation Protein Multimerization Proteins Receptors Reproducibility of Results Saliva Screening Small Molecule Libraries Structural models Structure Zinc Zinc compounds
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Summary:	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
ISSN:	1932-6203 1932-6203