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.

Do you wish to know more?



Comments

Post a Comment

Popular posts from this blog

Sequence Analysis is still sexy:Dual Descriptor Method for Biological Sequence Analysis

-
The emergence of “Systems Biology” in recent years highlights the systematic viewpoint of bio-system modeling. Building on such a background, Dual Descriptor Method, a generic methodology for biological sequence analysis is proposed. From a systematic perspective, Dual Descriptor is defined as a two element set of Composition Weight Map and Position Weight Function which aim at reflecting the composition and permutation information of a sequence. An alternate training algorithm is provided to get an optimum description of the building patterns of the sequences. In this paper , dual descriptor method has been applied to the analysis of two typical problems of molecular biology: gene identification and the prediction of protein function. Satisfactory and insightful results are achieved. Owing to the generality of this methodology, dual descriptor method has wide application perspective for many problems of pattern recognition, especially those involved in “Systems Biology”. Be a part of
Read more

Abbott Laboratories Buys Piramal Healthcare Limited Biz for $3.72B

-
Abbott May 21 announced a definitive agreement with Piramal Healthcare Limited to acquire full ownership of Piramal's Healthcare Solutions business (Domestic Formulations), a leader in the Indian branded generics market, for an up-front payment of $2.12 billion , plus $400 million annually for the next four years, giving Abbott the No. 1 position in the Indian pharmaceutical market. This further accelerates Abbott's emerging markets growth following the recent acquisition of Solvay Pharmaceuticals and announcements last week of Abbott's collaboration with Zydus Cadila as well as the creation of a new stand-alone Established Products Division to focus on expanding the global markets for its leading branded generics portfolio. "This strategic action will advance Abbott into the leading market position in India , one of the world's most attractive and rapidly growing markets," said Miles D. White , chairman and chief executive officer, Abbott. &quo
Read more

List of Cheminformatics Companies & Institutions

-
Accelrys ACD/Labs (Advanced Chemistry Development, Inc.) Afferent Systems Inc. Agilent Technologies Aureus Pharma Barnard Chemical Information Ltd. (John Barnard and Geoff Downs) SEE: digital chemistry Bio-Rad Laboratories BioReason BioSolveIT BlueObelisk.org Bruker Daltonics Inc. Cambridge Crystallographic Data Centre CambridgeSoft Corporation CARB Center for Advanced Research in Biotechnology (NIST/University of Maryland) Cengent Therapeutics (Genes to Leads). Acquired by Inncardio, Inc. Center for Molecular Modeling (NIH) Centre for Molecular and Biomolecular Informatics CMBI (formerly: CAOS/CAMM: Dutch National Center for Computer-Assisted Chemistry and Molecular Modelling) Cerep ChemAxon ChemDiv, Inc. (Chemical Diversity) Chemical Abstracts Service Chemical Computing Group, Inc. Chemical Simulations Group ChemInnovation Software ChemNavigator ChemSW (Chemistry Software for Windows, formerly: WindowChem) Chenomx Inc. CIS Chemical Information System CombiChem.net CompuChem C
Read more