دورية أكاديمية
In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening
| العنوان: | In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening |
|---|---|
| المؤلفون: | Maxime Louet, Sara Bitam, Naziha Bakouh, Yohan Bignon, Gabrielle Planelles, David Lagorce, Maria A. Miteva, Dominique Eladari, Jacques Teulon, Bruno O. Villoutreix |
| المصدر: | Scientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) |
| بيانات النشر: | Nature Portfolio, 2017. |
| سنة النشر: | 2017 |
| المجموعة: | LCC:Medicine LCC:Science |
| مصطلحات موضوعية: | Medicine, Science |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2045-2322 |
| العلاقة: | https://doaj.org/toc/2045-2322Test |
| DOI: | 10.1038/s41598-017-07794-5 |
| الوصول الحر: | https://doaj.org/article/4dc1bd937e734475b48e1b0e7b1ec36eTest |
| رقم الانضمام: | edsdoj.4dc1bd937e734475b48e1b0e7b1ec36e |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20452322 |
|---|---|
| DOI: | 10.1038/s41598-017-07794-5 |