Presentation Title

Studies of Amino Acid Mutations in Neuraminidase and Drug Resistance of Influenza Virus

Advisor Information

Haizhen Zhong

Location

UNO Criss Library, Room 231

Presentation Type

Oral Presentation

Start Date

7-3-2014 10:45 AM

End Date

7-3-2014 11:00 AM

Abstract

Homology modeling and docking methods were used to explore the effects of different mutants on antiviral drug binding to neuraminidase (NA), a protein important for influenza virus replication. Homology modeling was used to build models of S247G and H275T mutant strains. Other structurally available models of 3CKZ (H274Y), 4B7J (I223R), 3CL2 (N924S), and these two new models were aligned to the wild-type NA, 3B7E, using MOE. The structural alignments of these strains on MOE helped to identify the location of mutations in the binding pocket. To understand how these mutations affect the binding affinity, small molecules were built and docked to the different model proteins to determine binding affinity. Amongst these molecules were Zanamivir, Oseltamivir, and Peramivir, three current antiviral drugs. The Glide Dock program in MAESTRO measures how each mutation affects the binding of the small molecules, particularly our three antiviral drugs. In previous studies it was found that the active site of neuraminidase contains Arg371, Arg292, Arg118, and Arg152. Our docking studies not only confirmed amino acid residues Arg371, Arg152, Arg292, and Arg118 form hydrogen bindings to the small molecules, we also identified Asp151, Arg293, and Arg386 as new residues important for ligand binding. The importance of water molecules in ligand binding was confirmed by our observation that absence of water molecules significantly reduced binding affinity, thus emphasizing the significance of water-mediated hydrogen bondings in drug binding.

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Mar 7th, 10:45 AM Mar 7th, 11:00 AM

Studies of Amino Acid Mutations in Neuraminidase and Drug Resistance of Influenza Virus

UNO Criss Library, Room 231

Homology modeling and docking methods were used to explore the effects of different mutants on antiviral drug binding to neuraminidase (NA), a protein important for influenza virus replication. Homology modeling was used to build models of S247G and H275T mutant strains. Other structurally available models of 3CKZ (H274Y), 4B7J (I223R), 3CL2 (N924S), and these two new models were aligned to the wild-type NA, 3B7E, using MOE. The structural alignments of these strains on MOE helped to identify the location of mutations in the binding pocket. To understand how these mutations affect the binding affinity, small molecules were built and docked to the different model proteins to determine binding affinity. Amongst these molecules were Zanamivir, Oseltamivir, and Peramivir, three current antiviral drugs. The Glide Dock program in MAESTRO measures how each mutation affects the binding of the small molecules, particularly our three antiviral drugs. In previous studies it was found that the active site of neuraminidase contains Arg371, Arg292, Arg118, and Arg152. Our docking studies not only confirmed amino acid residues Arg371, Arg152, Arg292, and Arg118 form hydrogen bindings to the small molecules, we also identified Asp151, Arg293, and Arg386 as new residues important for ligand binding. The importance of water molecules in ligand binding was confirmed by our observation that absence of water molecules significantly reduced binding affinity, thus emphasizing the significance of water-mediated hydrogen bondings in drug binding.