Design drugs that circumvent viral drug resistance – mechanism behind Tamiflu resistance

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.

Oseltamivir (Tamiflu) is the main antiviral drug used to fight viral influenza outbreaks such as the recent swine flu (H1N1pdm) global pandemic and avian (H5N1) outbreak in Asia. Oseltamivir inhibits a protein on the surface of flu viruses called neuraminidase, which is responsible for releasing newly formed viruses. The rapid emergence of drug resistance in H5N1 avian flu (and recently the H1N1pdm strain) has already motivated numerous studies to understand how mutations render oseltamivir ineffective, but no focused investigation has yet elucidated the specific mechanism behind mutation-induced drug resistance. Here, large scale computer simulations are employed to study both H5N1 and H1N1pdm neuraminidase to answer the questions: how does N1-subtype neuraminidase bind oseltamivir, and how would mutations alter this process? The key finding revealed in our simulations is the discovery of oseltamivir binding to neuraminidase by a charged pathway on the protein surface. We suggest that point mutations may disrupt drug binding by interfering with this pathway. Our results explain the fundamental mechanism behind oseltamivir resistance and pave the way for the design of drugs that circumvent viral drug resistance.

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