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Title:H274Y's effect on oseltamivir resistance : what happens before the drug enters the binding site
Authors:Yusuf, Muhammad (Author)
Mohamed, Nornisah (Author)
Mohamad, Suriyati (Author)
Janežič, Dušanka (Author)
Damodaran, K. V. (Author)
Wahab, Habibah A. (Author)
Files:URL http://pubs.acs.org/doi/ipdf/10.1021/acs.jcim.5b00331
 
Language:English
Work type:Not categorized
Tipology:1.01 - Original Scientific Article
Organization:IAM - Andrej Marušič Institute
Abstract:Increased reports of oseltamivir (OTV)-resistant strains of the influenza virus, such as the H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies have been conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H274Y focused only on the drug-bound system, so the direct effects of the mutation on NA itself prior to drug binding still remain unclear. Therefore, molecular dynamics simulations of NA in apo form, followed by principal component analysis and interaction energy calculations, were performed to investigate the structural changes of the NA binding site as a result of the H274Y mutation. It was observed that the disruption of the NA binding site due to the H274Y mutation was initiated by the repulsive effect of Y274 on the 250-loop, which in turn altered the hydrogen-bonding network around residue 274. The rotated W295 side chain caused the upward movement of the 340-loop. Consequently, sliding box docking results suggested that the binding pathway of OTV was compromised because of the disruption of this binding site. This study also highlighted the importance of the functional group at C6 of the sialic acid mimicry. It is hoped that these results will improve the understanding of OTV resistance and shed some light on the design of a novel anti-influenza drug.
Keywords:influenza, neuraminidase, H274Y, oseltamivir, molecular dynamics
Year of publishing:2016
Number of pages:str. 82-100
Numbering:iss. 1, Vol. 56
ISSN:1549-9596
UDC:544.1
COBISS_ID:1538117060 Link is opened in a new window
DOI:10.1021/acs.jcim.5b00331 Link is opened in a new window
Views:1137
Downloads:58
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