Journal of Computer-Aided Molecular Design

, Volume 10, Issue 3, pp 233–246

A structural and energetics analysis of the binding of a series of N-acetylneuraminic-acid-based inhibitors to influenza virus sialidase

  • Neil R. Taylor
  • Mark von Itzstein
Research Paper

DOI: 10.1007/BF00355045

Cite this article as:
Taylor, N.R. & von Itzstein, M. Journal of Computer-Aided Molecular Design (1996) 10: 233. doi:10.1007/BF00355045


A molecular dynamics/energy-minimisation protocol has been used to analyse the structural and energetic effects of functional group substitution on the binding of a series of C4-modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid inhibitors to influenza virus sialidase. Based on the crystal structure of sialidase, a conformational searching protocol, incorporating multiple randomisation steps in a molecular dynamics simulation was used to generate a range of minimum-energy structures. The calculations were useful for predicting the number, location, and orientation of structural water molecules within protein-ligand complexes. Relative binding energies were calculated for the series of complexes using several empirical molecular modelling approaches. Energies were computed using molecular-mechanics-derived interactions as the sum of pairwise atomic nonbonded energies, and in a more rigorous manner including solvation effects as the change in total electrostatic energy of complexation, using a continuum-electrostatics (CE) approach. The CE approach exhibited the superior correlation with observed affinities. Both methods showed definite trends in observed and calculated binding affinities; in both cases inhibitors with a positively charged C4 substituent formed the tightest binding to the enzyme, as observed experimentally.


Calculated binding energiesMolecular mechanicsContinuum electrostaticsSialidaseInfluenza

Copyright information

© ESCOM Science Publishers B.V 1996

Authors and Affiliations

  • Neil R. Taylor
    • 1
  • Mark von Itzstein
    • 1
  1. 1.Department of Medicinal Chemistry, Victorian College of PharmacyMonash UniversityParkvilleAustralia