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Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor
Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual sc...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376056/ https://www.ncbi.nlm.nih.gov/pubmed/25047372 http://dx.doi.org/10.1038/srep05775 |
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author | Li, Min Tou, Weng Ieong Zhou, Hong Li, Fei Ren, Huiwen Chen, Calvin Yu-Chian Yang, Baoxue |
author_facet | Li, Min Tou, Weng Ieong Zhou, Hong Li, Fei Ren, Huiwen Chen, Calvin Yu-Chian Yang, Baoxue |
author_sort | Li, Min |
collection | PubMed |
description | Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual screening (HTVS) of 50000 small-molecular drug-like compounds identified 2319 hit compounds. These 2319 compounds were screened by high-throughput screening using an erythrocyte osmotic lysis assay. Based on the pharmacological data, putative UT-B binding sites were identified by structure-based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional characteristics under inhibitors treated and untreated conditions were simulated by molecular dynamics (MD). As the result, we identified four classes of compounds with UT-B inhibitory activity and predicted a human UT-B model, based on which computative binding sites were identified and validated. A novel potential mechanism of UT-B inhibitory activity was discovered by comparing UT-B from different species. Results suggest residue PHE198 in rat and mouse UT-B might block the inhibitor migration pathway. Inhibitory mechanisms of UT-B inhibitors and the functions of key residues in UT-B were proposed. The binding site analysis provides a structural basis for lead identification and optimization of UT-B inhibitors. |
format | Online Article Text |
id | pubmed-5376056 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53760562017-04-03 Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor Li, Min Tou, Weng Ieong Zhou, Hong Li, Fei Ren, Huiwen Chen, Calvin Yu-Chian Yang, Baoxue Sci Rep Article Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual screening (HTVS) of 50000 small-molecular drug-like compounds identified 2319 hit compounds. These 2319 compounds were screened by high-throughput screening using an erythrocyte osmotic lysis assay. Based on the pharmacological data, putative UT-B binding sites were identified by structure-based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional characteristics under inhibitors treated and untreated conditions were simulated by molecular dynamics (MD). As the result, we identified four classes of compounds with UT-B inhibitory activity and predicted a human UT-B model, based on which computative binding sites were identified and validated. A novel potential mechanism of UT-B inhibitory activity was discovered by comparing UT-B from different species. Results suggest residue PHE198 in rat and mouse UT-B might block the inhibitor migration pathway. Inhibitory mechanisms of UT-B inhibitors and the functions of key residues in UT-B were proposed. The binding site analysis provides a structural basis for lead identification and optimization of UT-B inhibitors. Nature Publishing Group 2014-07-22 /pmc/articles/PMC5376056/ /pubmed/25047372 http://dx.doi.org/10.1038/srep05775 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved 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 in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Li, Min Tou, Weng Ieong Zhou, Hong Li, Fei Ren, Huiwen Chen, Calvin Yu-Chian Yang, Baoxue Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title | Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title_full | Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title_fullStr | Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title_full_unstemmed | Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title_short | Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor |
title_sort | developing hypothetical inhibition mechanism of novel urea transporter b inhibitor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376056/ https://www.ncbi.nlm.nih.gov/pubmed/25047372 http://dx.doi.org/10.1038/srep05775 |
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