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Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation
GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitropheny...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831007/ https://www.ncbi.nlm.nih.gov/pubmed/27074918 http://dx.doi.org/10.1038/srep24240 |
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author | George Thompson, Alayna M. Ursu, Oleg Babkin, Petr Iancu, Cristina V. Whang, Alex Oprea, Tudor I. Choe, Jun-yong |
author_facet | George Thompson, Alayna M. Ursu, Oleg Babkin, Petr Iancu, Cristina V. Whang, Alex Oprea, Tudor I. Choe, Jun-yong |
author_sort | George Thompson, Alayna M. |
collection | PubMed |
description | GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. MSNBA inhibition was specific to GLUT5; this inhibitor did not affect the fructose transport of human GLUT2 or the glucose transport of human GLUT1-4 or bacterial GlcP(Se). In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a K(I) of 3.2 ± 0.4 μM. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity. |
format | Online Article Text |
id | pubmed-4831007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48310072016-04-19 Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation George Thompson, Alayna M. Ursu, Oleg Babkin, Petr Iancu, Cristina V. Whang, Alex Oprea, Tudor I. Choe, Jun-yong Sci Rep Article GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. MSNBA inhibition was specific to GLUT5; this inhibitor did not affect the fructose transport of human GLUT2 or the glucose transport of human GLUT1-4 or bacterial GlcP(Se). In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a K(I) of 3.2 ± 0.4 μM. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity. Nature Publishing Group 2016-04-14 /pmc/articles/PMC4831007/ /pubmed/27074918 http://dx.doi.org/10.1038/srep24240 Text en Copyright © 2016, Macmillan Publishers Limited 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 George Thompson, Alayna M. Ursu, Oleg Babkin, Petr Iancu, Cristina V. Whang, Alex Oprea, Tudor I. Choe, Jun-yong Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title | Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title_full | Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title_fullStr | Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title_full_unstemmed | Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title_short | Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation |
title_sort | discovery of a specific inhibitor of human glut5 by virtual screening and in vitro transport evaluation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831007/ https://www.ncbi.nlm.nih.gov/pubmed/27074918 http://dx.doi.org/10.1038/srep24240 |
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