Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems

Abstract Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose...

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Autores principales:	Sina Schmidl, Oleg Ursu, Cristina V. Iancu, Mislav Oreb, Tudor I. Oprea, Jun-yong Choe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a3ca6807862349959215bc5d361e1f6c
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spelling	oai:doaj.org-article:a3ca6807862349959215bc5d361e1f6c2021-12-02T16:10:50ZIdentification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems10.1038/s41598-021-93063-52045-2322https://doaj.org/article/a3ca6807862349959215bc5d361e1f6c2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93063-5https://doaj.org/toc/2045-2322Abstract Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi–Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.Sina SchmidlOleg UrsuCristina V. IancuMislav OrebTudor I. OpreaJun-yong ChoeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sina Schmidl Oleg Ursu Cristina V. Iancu Mislav Oreb Tudor I. Oprea Jun-yong Choe Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
description	Abstract Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi–Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.
format	article
author	Sina Schmidl Oleg Ursu Cristina V. Iancu Mislav Oreb Tudor I. Oprea Jun-yong Choe
author_facet	Sina Schmidl Oleg Ursu Cristina V. Iancu Mislav Oreb Tudor I. Oprea Jun-yong Choe
author_sort	Sina Schmidl
title	Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
title_short	Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
title_full	Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
title_fullStr	Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
title_full_unstemmed	Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
title_sort	identification of new glut2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a3ca6807862349959215bc5d361e1f6c
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Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems

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