Comparative binding energy (COMBINE) analysis
of influenza neuraminidase-inhibitor complexes
Wang T, Wade RC.
European Molecular Biology Laboratory, Meyerhofstrasse 1, 69012 Heidelberg,
Germany.
Neuraminidase is a surface glycoprotein of influenza viruses that cleaves
terminal sialic acids from carbohydrates. It is critical for viral release
from infected cells and facilitates viral spread in the respiratory tract.
The catalytic active site of neuraminidase is highly conserved in all type
A and B influenza viruses, making it an excellent target for antiinfluenza
drug design. Indeed, neuraminidase inhibitors have recently become available
in the clinic for the treatment of influenza. Here, we describe the use of
3D structures of neuraminidase-inhibitor complexes to derive quantitative
structure-activity relationships (QSARs) to aid understanding of the mechanism
of inhibition and the discovery of new inhibitors. Crystal structures of
neuraminidase-inhibitor complexes were used alongside modeled complexes to
derive QSAR models by COMparative BINding Energy (COMBINE) analysis (Ortiz,
A. R.; Pisabarro, M. T.; Gago, F.; Wade, R. C. J. Med. Chem. 1995, 38, 2681-2691).
The neuraminidase proteins studied include type A subtypes N2 and N9 (which
have ca. 50% sequence identity) and an active site mutant of the N9 subtype.
The inhibitors include sialic acid and benzoic acid analogues with diverse
frameworks and substitution groups. By considering the contributions of the
protein residues and a key water molecule to the electrostatic and van der
Waals intermolecular interaction energies, a predictive and robust QSAR model
for binding to type A neuraminidase was obtained. In this QSAR model, 12
protein residues and 1 bound water molecule are highlighted as particularly
important for inhibitory activity. This QSAR model provides guidelines for
structural modification of current inhibitors and the design of novel inhibitors
in order to optimize inhibitory activity.