A selective class of inhibitors for the CLC-Ka chloride ion channel.

Autor:	Koster AK; Department of Chemistry, Stanford University, Stanford, CA 94305.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305., Wood CAP; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305., Thomas-Tran R; Department of Chemistry, Stanford University, Stanford, CA 94305., Chavan TS; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305., Almqvist J; Department of Cell and Molecular Biology, Uppsala University, 751 24 Uppsala, Sweden., Choi KH; Materials and Life Science Research Division, Korea Institute of Science and Technology, 02792 Seoul, Republic of Korea., Du Bois J; Department of Chemistry, Stanford University, Stanford, CA 94305; jdubois@stanford.edu maduke@stanford.edu., Maduke M; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; jdubois@stanford.edu maduke@stanford.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 May 22; Vol. 115 (21), pp. E4900-E4909. Date of Electronic Publication: 2018 Apr 18.
DOI:	10.1073/pnas.1720584115
Abstrakt:	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 ∼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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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