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Application of the fragment molecular orbital method to discover novel natural products for prion disease
Conformational conversion of the normal cellular isoform of the prion protein PrP(C) into an infectious isoform PrP(Sc) causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117342/ https://www.ncbi.nlm.nih.gov/pubmed/30166585 http://dx.doi.org/10.1038/s41598-018-31080-7 |
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author | Choi, Jiwon Kim, Hyo-Jin Jin, Xuemei Lim, Hocheol Kim, Songmi Roh, In-Soon Kang, Hae-Eun No, Kyoung Tai Sohn, Hyun-Joo |
author_facet | Choi, Jiwon Kim, Hyo-Jin Jin, Xuemei Lim, Hocheol Kim, Songmi Roh, In-Soon Kang, Hae-Eun No, Kyoung Tai Sohn, Hyun-Joo |
author_sort | Choi, Jiwon |
collection | PubMed |
description | Conformational conversion of the normal cellular isoform of the prion protein PrP(C) into an infectious isoform PrP(Sc) causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrP(C) binding site, and effectively reduced PrP(Sc) levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies. |
format | Online Article Text |
id | pubmed-6117342 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61173422018-09-05 Application of the fragment molecular orbital method to discover novel natural products for prion disease Choi, Jiwon Kim, Hyo-Jin Jin, Xuemei Lim, Hocheol Kim, Songmi Roh, In-Soon Kang, Hae-Eun No, Kyoung Tai Sohn, Hyun-Joo Sci Rep Article Conformational conversion of the normal cellular isoform of the prion protein PrP(C) into an infectious isoform PrP(Sc) causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrP(C) binding site, and effectively reduced PrP(Sc) levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies. Nature Publishing Group UK 2018-08-30 /pmc/articles/PMC6117342/ /pubmed/30166585 http://dx.doi.org/10.1038/s41598-018-31080-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Choi, Jiwon Kim, Hyo-Jin Jin, Xuemei Lim, Hocheol Kim, Songmi Roh, In-Soon Kang, Hae-Eun No, Kyoung Tai Sohn, Hyun-Joo Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title | Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title_full | Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title_fullStr | Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title_full_unstemmed | Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title_short | Application of the fragment molecular orbital method to discover novel natural products for prion disease |
title_sort | application of the fragment molecular orbital method to discover novel natural products for prion disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117342/ https://www.ncbi.nlm.nih.gov/pubmed/30166585 http://dx.doi.org/10.1038/s41598-018-31080-7 |
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