Mapping ligand binding pockets in ClC-1 channels through an integrated in silico and experimental approach using anthracene-9-carboxylic acid and niflumic acid

Despite the fact that chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is rather limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle fibers and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no useful activator exists. The absence of a ClC-1 structure and the limited information regarding the binding pockets in CLC channels hamper the identification of improved modulators.