Background and Purpose: Many structurally and therapeutically diverse drugs block the human ether-à-go-go related gene (HERG) potassium channel, predisposing patients to an increased risk of arrythmias and sudden cardiac death. Many drugs show state-dependence of block, exhibiting a greater preference for block of the inactivated state. Five key residues within the central pore cavity of HERG have been implicated in drug binding. However, whether drugs bind differently to these key residues to dictate preference for the inactivated over the open state is not known. Experimental Approach: We used the SyncroPatch 384PE, automated patch clamp platform to measure how drug block was impacted by point mutations at residues T623, S624, Y652, and F656 when introduced into wild-type HERG (preferentially occupies the inactivated state) and N588K-HERG (preferentially occupies the open state) channels at depolarised potentials. Key Results: Mutations to Y652 and F656, that abolished aromatic and hydrophobic characteristics respectively, reduced drug binding in both WT and N588K backgrounds. The S624A mutation attenuated block by cisapride, astemizole, and quinidine in the WT background but not in the N588K background. Conclusion and Implications: We suggest that relative movements between the polar S624 sidechain and the aromatic Y652 and F656 sidechains in WT (inactivated) compared to N588K (open) channels can explain preferential binding to the inactivated state. An improved understanding of the structural basis of where and how drugs bind to HERG channels should facilitate efforts to reduce inadvertent HERG drug block during the drug development process.