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Insights into structure and activity of natural compound inhibitors of pneumolysin

Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with dif...

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Autores principales: Li, Hongen, Zhao, Xiaoran, Deng, Xuming, Wang, Jianfeng, Song, Meng, Niu, Xiaodi, Peng, Liping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292752/
https://www.ncbi.nlm.nih.gov/pubmed/28165051
http://dx.doi.org/10.1038/srep42015
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author Li, Hongen
Zhao, Xiaoran
Deng, Xuming
Wang, Jianfeng
Song, Meng
Niu, Xiaodi
Peng, Liping
author_facet Li, Hongen
Zhao, Xiaoran
Deng, Xuming
Wang, Jianfeng
Song, Meng
Niu, Xiaodi
Peng, Liping
author_sort Li, Hongen
collection PubMed
description Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with differential activity, were discovered via haemolysis assay. To explore the key factor of the conformation for the inhibition activity, the interactions between five natural compound inhibitors with differential activity and pneumolysin were reported using molecular modelling, the potential of mean force profiles. Interestingly, it is found that incorporation of the single bond (C22-C23-C24-C25) to replace the double bond (hydrocarbon sidechain) improved the anti-haemolytic activity. In view of the molecular modelling, binding of the five inhibitors to the conserved loop region (Val372, Leu460, and Tyr461) of the cholesterol binding sites led to stable complex systems, which was consistent with the result of β-sitosterol. Owing to the single bond (C22-C23-C24-C25), campesterol and brassicasterol could form strong interactions with Val372 and show higher anti-haemolytic activity, which indicated that the single bond (C22-C23-C24-C25) in inhibitors was required for the anti-haemolytic activity. Overall, the current molecular modelling work provides a starting point for the development of rational design and higher activity pneumolysin inhibitors.
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spelling pubmed-52927522017-02-10 Insights into structure and activity of natural compound inhibitors of pneumolysin Li, Hongen Zhao, Xiaoran Deng, Xuming Wang, Jianfeng Song, Meng Niu, Xiaodi Peng, Liping Sci Rep Article Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with differential activity, were discovered via haemolysis assay. To explore the key factor of the conformation for the inhibition activity, the interactions between five natural compound inhibitors with differential activity and pneumolysin were reported using molecular modelling, the potential of mean force profiles. Interestingly, it is found that incorporation of the single bond (C22-C23-C24-C25) to replace the double bond (hydrocarbon sidechain) improved the anti-haemolytic activity. In view of the molecular modelling, binding of the five inhibitors to the conserved loop region (Val372, Leu460, and Tyr461) of the cholesterol binding sites led to stable complex systems, which was consistent with the result of β-sitosterol. Owing to the single bond (C22-C23-C24-C25), campesterol and brassicasterol could form strong interactions with Val372 and show higher anti-haemolytic activity, which indicated that the single bond (C22-C23-C24-C25) in inhibitors was required for the anti-haemolytic activity. Overall, the current molecular modelling work provides a starting point for the development of rational design and higher activity pneumolysin inhibitors. Nature Publishing Group 2017-02-06 /pmc/articles/PMC5292752/ /pubmed/28165051 http://dx.doi.org/10.1038/srep42015 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Li, Hongen
Zhao, Xiaoran
Deng, Xuming
Wang, Jianfeng
Song, Meng
Niu, Xiaodi
Peng, Liping
Insights into structure and activity of natural compound inhibitors of pneumolysin
title Insights into structure and activity of natural compound inhibitors of pneumolysin
title_full Insights into structure and activity of natural compound inhibitors of pneumolysin
title_fullStr Insights into structure and activity of natural compound inhibitors of pneumolysin
title_full_unstemmed Insights into structure and activity of natural compound inhibitors of pneumolysin
title_short Insights into structure and activity of natural compound inhibitors of pneumolysin
title_sort insights into structure and activity of natural compound inhibitors of pneumolysin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292752/
https://www.ncbi.nlm.nih.gov/pubmed/28165051
http://dx.doi.org/10.1038/srep42015
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