Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs

Blockade of hERG K+ channels in the heart is an unintentional side effect of many drugs and can induce cardiac arrhythmia and sudden death. For this reason, most pharmaceutical companies screen compounds for hERG channel activity early in the drug discovery/development process. A detailed understanding of the drug binding site(s) on the hERG channel could enable rational design of future medications devoid of this unwanted side effect. Towards this goal, we have used site-directed mutagenesis to identify several residues of the hERG channel that comprise a common drug binding site. The initial Ala-scan identified several residues located in the S6 domain (Tyr652, Phe656) and the base of the pore helix (Thr623, Ser624, Val625) as important sites of interaction. Here, we review studies that refine our understanding of the physicochemical basis of interaction by structurally diverse drugs with aromatic residues in the S6 domain. Our findings suggest that the position of Tyr652 and Phe656 in hERG is optimal for interaction with multiple drugs, Tyr652 is an important determinant of voltage-dependent block, and the hydrophobic surface area of residue 656 and aromaticity of residue 652 are the physicochemical features required for high-affinity block by MK-499, cisapride and terfenadine.