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A selective class of inhibitors for the CLC-Ka chloride ion channel
Stanford Univ, Dept Chem, Stanford, CA 94305 USA;Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA.
Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA.
Stanford Univ, Dept Chem, Stanford, CA 94305 USA.
Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA.
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 21, p. E4900-E4909Article in journal (Refereed) Published
Abstract [en]

CLC proteins are a ubiquitously expressed family of chloride-selective ion channels and transporters. A dearth of pharmacological tools for modulating CLC gating and ion conduction limits investigations aimed at understanding CLC structure/function and physiology. Herein, we describe the design, synthesis, and evaluation of a collection of N-arylated benzimidazole derivatives (BIMs), one of which (BIM1) shows unparalleled (>20-fold) selectivity for CLC-Ka over CLC-Kb, the two most closely related human CLC homologs. Computational docking to a CLC-Ka homology model has identified a BIM1 binding site on the extracellular face of the protein near the chloride permeation pathway in a region previously identified as a binding site for other less selective inhibitors. Results from site-directed mutagenesis experiments are consistent with predictions of this docking model. The residue at position 68 is 1 of only similar to 20 extracellular residues that differ between CLC-Ka and CLC-Kb. Mutation of this residue in CLC-Ka and CLC-Kb (N68D and D68N, respectively) reverses the preference of BIM1 for CLC-Ka over CLC-Kb, thus showing the critical role of residue 68 in establishing BIM1 selectivity. Molecular docking studies together with results from structure-activity relationship studies with 19 BIM derivatives give insight into the increased selectivity of BIM1 compared with other inhibitors and identify strategies for further developing this class of compounds.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2018. Vol. 115, no 21, p. E4900-E4909
Keywords [en]
chloride channel, molecular probes, electrophysiology
National Category
Biological Sciences
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URN: urn:nbn:se:uu:diva-357277DOI: 10.1073/pnas.1720584115ISI: 000432663000022PubMedID: 29669921OAI: oai:DiVA.org:uu-357277DiVA, id: diva2:1239652
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VINNOVAAvailable from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-17Bibliographically approved

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