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Analysis of inhibitor binding in influenza virus neuraminidase

¹ Biomolecular Research Institute, Parkville, Victoria 3052, Australia
² Department of Medicinal Chemistry, Monash University, Parkville, Victoria 3052, Australia

Reprint requests to: Dr. Brian J. Smith, Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria 3052, Australia; e-mail: brian.smith{at}bioresi.com.au; fax: 61-3-9662-7347.

2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) is a transition state analog inhibitor of influenza virus neuraminidase (NA). Replacement of the hydroxyl at the C₉ position in DANA and 4-amino-DANA with an amine group, with the intention of taking advantage of an increased electrostatic interaction with a conserved acidic group in the active site to improve inhibitor binding, significantly reduces the inhibitor activity of both compounds. The three-dimensional X-ray structure of the complexes of these ligands and NA was obtained to 1.4 Å resolution and showed that both ligands bind isosterically to DANA. Analysis of the geometry of the ammonium at the C₄ position indicates that Glu119 may be neutral when these ligands bind. A computational analysis of the binding energies indicates that the substitution is successful in increasing the energy of interaction; however, the gains that are made are not sufficient to overcome the energy that is required to desolvate that part of the ligand that comes in contact with the protein.

Keywords: Influenza virus; neuraminidase inhibitors; electrostatics; X-ray crystal structures; binding energies; molecular modeling

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