Paper Info
Title
Binding mechanism of oseltamivir and influenza neuraminidase suggests perspectives for the design of new anti-influenza drugs
Abstract
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.
Year
DOI
Venue
2022
10.1371/JOURNAL.PCBI.1010343
PLoS Computational Biology
DocType
Volume
Issue
Journal
18
7
ISSN
Citations 
PageRank 
1553-7358
0
0.34
References 
Authors
0
19
Name
Order
Citations
PageRank
Jiaye Tao100.34
Heping Wang200.34
Wenjian Wang300.34
Na Mi400.34
Wei Zhang512.39
Qiujia Wen600.34
Jiajing Ouyang700.34
Xinyun Liang800.34
Min Chen900.34
Wentao Guo1000.34
Guoming Li1100.34
Y. J. Liu121116.87
Hanning Zhao1300.34
Xin Wang14018.25
Xuemeng Li1500.34
Shengjun Feng1600.34
Xinguang Liu1700.34
Zhiwei He1800.34
Zuguo Zhao1900.34