In:
PLOS Computational Biology, Public Library of Science (PLoS), Vol. 18, No. 7 ( 2022-7-28), p. e1010343-
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.
Type of Medium:
Online Resource
ISSN:
1553-7358
DOI:
10.1371/journal.pcbi.1010343
DOI:
10.1371/journal.pcbi.1010343.g001
DOI:
10.1371/journal.pcbi.1010343.g002
DOI:
10.1371/journal.pcbi.1010343.g003
DOI:
10.1371/journal.pcbi.1010343.g004
DOI:
10.1371/journal.pcbi.1010343.g005
DOI:
10.1371/journal.pcbi.1010343.g006
DOI:
10.1371/journal.pcbi.1010343.g007
DOI:
10.1371/journal.pcbi.1010343.t001
DOI:
10.1371/journal.pcbi.1010343.s001
DOI:
10.1371/journal.pcbi.1010343.s002
DOI:
10.1371/journal.pcbi.1010343.s003
DOI:
10.1371/journal.pcbi.1010343.s004
DOI:
10.1371/journal.pcbi.1010343.s005
DOI:
10.1371/journal.pcbi.1010343.s006
DOI:
10.1371/journal.pcbi.1010343.s007
DOI:
10.1371/journal.pcbi.1010343.s008
DOI:
10.1371/journal.pcbi.1010343.s009
DOI:
10.1371/journal.pcbi.1010343.s010
DOI:
10.1371/journal.pcbi.1010343.s011
DOI:
10.1371/journal.pcbi.1010343.s012
DOI:
10.1371/journal.pcbi.1010343.s013
DOI:
10.1371/journal.pcbi.1010343.s014
DOI:
10.1371/journal.pcbi.1010343.s015
DOI:
10.1371/journal.pcbi.1010343.r001
DOI:
10.1371/journal.pcbi.1010343.r002
DOI:
10.1371/journal.pcbi.1010343.r003
DOI:
10.1371/journal.pcbi.1010343.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2193340-6
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