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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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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. |
format | Online Article Text |
id | pubmed-5292752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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