Analysis of inhibitor binding in influenza virus neuraminidase

Smith, BJ Colman, PM Von Itzstein, M Danylec, B Varghese, JN

Bj. Smith et al., Analysis of inhibitor binding in influenza virus neuraminidase, PROTEIN SCI, 10(4), 2001, pp. 689-696

52

INGLESE

Article

Biochemistry & Biophysics

PROTEIN SCIENCE

0961-8368 → ACNP

10

4

2001

689 - 696

ISI

0961-8368(200104)10:4<689:AOIBII>2.0.ZU;2-4

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 C-9 position in DANA and 4-amino-DANA with an amine group, with the intention of taking advantage of an increased electrostatic intera ction with a conserved acidic group in the active site to improve inhibitor binding, significantly reduces the inhibitor activity of both compounds. T he three-dimensional X-ray structure of the complexes of these ligands and NA was obtained to 1.4 Angstrom resolution and showed that both ligands bin d isosterically to DANA. Analysis of the geometry of the ammonium at the C- 4 position indicates that Glu119 may be neutral when these ligands bind. A computational analysis of the binding energies indicates that the substitut ion is successful in increasing the energy of interaction; however, the gai ns 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 protei n.