Abstract
Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 “avian” and H1N1pdm “swine” flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms.
Highlights
Oseltamivir, better known by its commercial name Tamiflu, is currently the most important antiviral drug employed to combat the flu virus [1]
From these structures it has been suggested that oseltamivir resistance due to point mutations arise from a destabilization of the hydrophobic packing that binds oseltamivir tightly within the neuraminidase active site [12]
We suggest that our observations regarding the oseltamivir binding behavior of H5N1 should apply for H1N1pdm, since the two proteins have very high sequence identity (91.47%) and share a conserved drug binding site
Summary
Oseltamivir, better known by its commercial name Tamiflu, is currently the most important antiviral drug employed to combat the flu virus [1]. Drug binding is a dynamic process and computational studies used the crystal structures as starting points to shed light on exactly how protein flexibility and point mutations influence drug-protein endpoint interactions [8,9,10,11] Despite these initial inroads of studies based on molecular dynamics (MD) simulations, the current understanding of the mechanism behind drug resistance remains incomplete and some conclusions are conflicting. In one study [10] it was reported that the H274Y mutation disrupts E276-R224 salt bridges that accommodate the hydrophobic pentyl group of oseltamivir, while in another study [8] the same salt bridges were observed to be stable Up to this point, all proposed mechanisms for oseltamivir resistance have focused mainly on effects of mutations on the SA binding site and equilibrium drug binding affinities
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