In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening

Abstract The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In o...

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Autores principales:	Maxime Louet, Sara Bitam, Naziha Bakouh, Yohan Bignon, Gabrielle Planelles, David Lagorce, Maria A. Miteva, Dominique Eladari, Jacques Teulon, Bruno O. Villoutreix
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4dc1bd937e734475b48e1b0e7b1ec36e
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spelling	oai:doaj.org-article:4dc1bd937e734475b48e1b0e7b1ec36e2021-12-02T15:04:52ZIn silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening10.1038/s41598-017-07794-52045-2322https://doaj.org/article/4dc1bd937e734475b48e1b0e7b1ec36e2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07794-5https://doaj.org/toc/2045-2322Abstract The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In order to gain new insights into the sequence-structure-function relationships of this channel, to investigate possible impacts of amino-acid substitutions, and to design novel inhibitors, we first built a structural model of the human ClC-Kb channel using comparative modeling strategies. We combined in silico and in vitro techniques to analyze amino acids involved in the chloride ion pathway as well as to rationalize the possible role of several clinically observed mutations leading to the Bartter syndrome type 3. Virtual screening and drug repositioning computations were then carried out. We identified six novel molecules, including 2 approved drugs, diflusinal and loperamide, with Kd values in the low micromolar range, that block the human ClC-Kb channel and that could be used as starting point to design novel chemical probes for this potential therapeutic target.Maxime LouetSara BitamNaziha BakouhYohan BignonGabrielle PlanellesDavid LagorceMaria A. MitevaDominique EladariJacques TeulonBruno O. VilloutreixNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maxime Louet Sara Bitam Naziha Bakouh Yohan Bignon Gabrielle Planelles David Lagorce Maria A. Miteva Dominique Eladari Jacques Teulon Bruno O. Villoutreix In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
description	Abstract The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In order to gain new insights into the sequence-structure-function relationships of this channel, to investigate possible impacts of amino-acid substitutions, and to design novel inhibitors, we first built a structural model of the human ClC-Kb channel using comparative modeling strategies. We combined in silico and in vitro techniques to analyze amino acids involved in the chloride ion pathway as well as to rationalize the possible role of several clinically observed mutations leading to the Bartter syndrome type 3. Virtual screening and drug repositioning computations were then carried out. We identified six novel molecules, including 2 approved drugs, diflusinal and loperamide, with Kd values in the low micromolar range, that block the human ClC-Kb channel and that could be used as starting point to design novel chemical probes for this potential therapeutic target.
format	article
author	Maxime Louet Sara Bitam Naziha Bakouh Yohan Bignon Gabrielle Planelles David Lagorce Maria A. Miteva Dominique Eladari Jacques Teulon Bruno O. Villoutreix
author_facet	Maxime Louet Sara Bitam Naziha Bakouh Yohan Bignon Gabrielle Planelles David Lagorce Maria A. Miteva Dominique Eladari Jacques Teulon Bruno O. Villoutreix
author_sort	Maxime Louet
title	In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
title_short	In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
title_full	In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
title_fullStr	In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
title_full_unstemmed	In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
title_sort	in silico model of the human clc-kb chloride channel: pore mapping, biostructural pathology and drug screening
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4dc1bd937e734475b48e1b0e7b1ec36e
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In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening

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