Viral neuraminidase acts catalytically to cleave a terminal sialic acid moiety from host-cell surface receptors enabling the release of nascent influenza viruses and subsequent infection of new cells.  Therefore, drugs that function as neuraminidase inhibitors represent an attractive antiviral strategy.  Recently, however, mutant neuraminidases have demonstrated oseltamivir resistance.   To understand the molecular features of a mutant neuraminidase (H274) that give rise to such resistance, classical simulations were utilized to compare the binding trajectories of oseltamivir and sialic acid to both wild type and mutant neuraminidases. Clustered diffusional approaches from Brownian dynamics simulations were used to initiate molecular dynamics simulations proximal to the neuraminidase surface. Snapshots of the complex were then processed using the Molecular Mechanics/Generalized Born Surface Area method in order to elucidate specific binding pathways for both ligands.

Calculation of the association trajectories of oseltamivir and sialic acid to wild type and H274Y viral neuraminidase

249th National Meeting (2015)

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