Proceedings of the National Academy of Sciences · 2018 · 23 citations · 31 references
MedicineMedicinal ChemistryPharmacologyDrug DesignMolecular PharmacologyStructural BiologyIon Channel PharmacologyIon Channel PhysiologyIon PermeationLigand BindingMolecular DockingProtein-ligand DockingBenzimidazole ChemistryChloride Channel PharmacologyChloride Channel PhysiologyDirected MutagenesisDrug Binding To Ion ChannelsIon Channel Structure-function RelationshipsIon Permeation MechanismsIon Permeation Pathway
-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.
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