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Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening
Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to vi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615092/ https://www.ncbi.nlm.nih.gov/pubmed/23565147 http://dx.doi.org/10.1371/journal.pone.0059315 |
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author | Jia, JianMin Xu, XiaoLi Liu, Fang Guo, XiaoKe Zhang, MingYe Lu, MengChen Xu, LiLi Wei, JinLian Zhu, Jia Zhang, ShengLie Zhang, ShengMiao Sun, HaoPeng You, QiDong |
author_facet | Jia, JianMin Xu, XiaoLi Liu, Fang Guo, XiaoKe Zhang, MingYe Lu, MengChen Xu, LiLi Wei, JinLian Zhu, Jia Zhang, ShengLie Zhang, ShengMiao Sun, HaoPeng You, QiDong |
author_sort | Jia, JianMin |
collection | PubMed |
description | Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC(50) value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization. |
format | Online Article Text |
id | pubmed-3615092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36150922013-04-05 Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening Jia, JianMin Xu, XiaoLi Liu, Fang Guo, XiaoKe Zhang, MingYe Lu, MengChen Xu, LiLi Wei, JinLian Zhu, Jia Zhang, ShengLie Zhang, ShengMiao Sun, HaoPeng You, QiDong PLoS One Research Article Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC(50) value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization. Public Library of Science 2013-04-02 /pmc/articles/PMC3615092/ /pubmed/23565147 http://dx.doi.org/10.1371/journal.pone.0059315 Text en © 2013 Jia et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Jia, JianMin Xu, XiaoLi Liu, Fang Guo, XiaoKe Zhang, MingYe Lu, MengChen Xu, LiLi Wei, JinLian Zhu, Jia Zhang, ShengLie Zhang, ShengMiao Sun, HaoPeng You, QiDong Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title | Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title_full | Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title_fullStr | Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title_full_unstemmed | Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title_short | Identification, Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening |
title_sort | identification, design and bio-evaluation of novel hsp90 inhibitors by ligand-based virtual screening |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615092/ https://www.ncbi.nlm.nih.gov/pubmed/23565147 http://dx.doi.org/10.1371/journal.pone.0059315 |
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