Abstract The recent wide spreading of the H5N1
avian influenza virus (AIV) in Asia, Europe and Africa
and its ability to cause fatal infections in human has
raised serious concerns about a pending global
flu pandemic. Neuraminidase (NA) inhibitors are
currently the only option for treatment or prophylaxis
in humans infected with this strain. However, drugs
currently on the market often meet with rapidly
emerging resistant mutants and only have limited
application as inadequate supply of synthetic material.
To dig out helpful information for designing potent
inhibitors with novel structures against the NA, we
used automated docking, CoMFA, CoMSIA, and
HQSAR methods to investigate the quantitative
structureĘCactivity relationship for 126 NA inhibitors
(NIs) with great structural diversities and wide range of
bioactivities against influenza A virus. Based on the
binding conformations discovered via molecular
docking into the crystal structure of NA, CoMFA and
CoMSIA models were successfully built with the crossvalidated
q2 of 0.813 and 0.771, respectively. HQSAR
was also carried out as a complementary study in that
HQSAR technique does not require 3D information of
these compounds and could provide a detailed molecular
fragment contribution to the inhibitory activity.
These models also show clearly how steric, electrostatic,
hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and
CoMSIA field distributions are found to be in well
agreement with the structural characteristics of the
corresponding binding sites. Therefore, the final
3D-QSAR models and the information of the inhibitorĘC
enzyme interaction should be useful in developing
novel potent NA inhibitors.