Background: With cases of emergence of drug resistance to the current competitive inhibitors
of neuraminidase (NA) such as oseltamivir and zanamavir, there is a present need for an alternative
approach in the treatment of avian influenza. With this in view, some flavones and chalcones were designed
based on quercetin, the most active naturally occurring noncompetitive inhibitor.
Objective: We attempt to understand the binding of quercetin to H5N1-NA, and synthetic analogs of
quercetin namely flavones and its precursors the chalcones using computational tools.
Methods: Molecular docking was done using Libdock. Molecular dynamics (MD) simulations were
performed using Amber14. We synthesized the two compounds; their structures were confirmed by infrared
spectroscopy, 1H-NMR, and mass spectrometry. These molecules were then tested for H5N1-NA
inhibition and kinetics of inhibition.
Results: Molecular docking studies yielded two compounds i.e., 4’-methoxyflavone and 2’-hydroxy-4-methoxychalcone, as promising leads which identified them as binders of the 150-cavity of NA. Furthermore,
MD simulation studies revealed that quercetin and the two compounds bind and hold the 150
loop in its open conformation, which ultimately perturbs the binding of sialic acid in the catalytic site.
Estimation of the free energy of binding by MM-PBSA portrays quercetin as more potent than chalcone
and flavone. These molecules were then determined as non-competitive inhibitors from the Lineweaver-Burk plots rendered from the enzyme kinetic studies.
Conclusion: We conclude that non-competitive type of inhibition, as shown in this study, can serve as
an effective method to block NA and evade the currently seen drug resistance.