Similarity of binding modes of charged and neutral blockers. (A) Cytoplasmic and side views at superposition of the channel-bound ligands. The charged nitrogens and ligand-bound sodium ions are blue and yellow, respectively. The carbon atoms at the opposite end of the ligands are gray. Note the clustering of blue/yellow atoms at the Na_III site and gray atoms at F⁴ⁱ¹⁵. The gray outlier belongs to bisphenol A, which lacks an aromatic ring protruding into the pore. (B) Scheme of ligand–channel interactions. The charged nitrogen or ligand-bound sodium ion interacts with the ring of carbonyls ^p48O=C (Na_III site) indicated by the red rectangle. The aromatic groups interact with hydrophobic residues in the inner pore (gray rectangle), among which F⁴ⁱ¹⁵ plays the major role. (C) Lidocaine and sodium-bound CMZ have a common pharmacophore.