The Influenza A enzyme Neuraminidase (NA) cleaves terminal sialic acid moities from the host cell-surface receptors and allows for the release of new virions, an essential step in the influenza lifecycle. In this work, we have utilized Brownian Dynamic (BD) simulations to investigate the binding kinetics of the NA competitive inhibitors, oseltamivir, peramivir and zanamivir, as well as its natural substrate, sialic acid. Despite the similarities in structures among the NA inhibitors, the kinetics of oseltamivir binding to the active site of NA were calculated to be approximately a thousand times faster than the two other ligands. Previous research in our laboratory has shown that the difference in the binding kinetics among the ligands was primarily due to a difference in the calculated desolvation energies. Additionally, qualitative observations suggested that oseltamivir achieved bound configurations with two possible orientations while the other ligands demonstrated only one dominant orientation with the desolvation on. To investigate these discrepancies, we utilized BD simulations to quantitatively measure the orientational distributions of the ligands and their energetics. In additional to our previously reported findings of the energetics of association, we have reevaluated the sensitivity of the calculations to the starting conformations of the ligands, an important consideration in these rigid body simulations. The effects of the starting conformations on the effective charges, the electrostatic potential grids, and the final distribution of associated ligands will be presented.<br/>

Investigation of different binding kinetics among the neuraminidase inhibitors

253rd National Meeting (2017)

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