Research Paper

Journal of Computer-Aided Molecular Design

, Volume 10, Issue 3, pp 233-246

First online:

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

  • Neil R. TaylorAffiliated withDepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University
  • , Mark von ItzsteinAffiliated withDepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University

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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 energies Molecular mechanics Continuum electrostatics Sialidase Influenza