We present it new docking model for H ERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms it hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a pi-pi interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of H ERG residue F656. The previous model assumes two interactions Such that (1) a protonated nitrogen of the channel blocker forms a cation-pi interaction with the aromatic ring of HERG residue Y652; and (2) it hydrophobic group of the channel blocker forms it hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based oil the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC(50) value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show only two binding interactions). If Our novel hypothesis is correct, the distributions should differ between Groups 1 and 2. Consistent with our hypothesis, the two groups differed with regard to pIC(50), and the group having more predicted interactions with the HERG channel had a higher mean pIC50 value. Although additional work will be required to further validate Our hypothesis, this improved understanding of the H ERG channel blocker binding mode may help promote the development of in silico predictions methods for identifying potential HERG channel blockers. (c) 2006 Elsevier Inc. All rights reserved.