Development and Validation Studies of Universal Pharmacophore Models for hERG Channel Openers

The intra-cavitary drug blockade of hERG channel, a common off-target for many drugs, have been extensively studied both experimentally and theoretically. Structurally diverse ligands inadvertent blockade of rapid component of delayed rectifying K+ currents are potentially pro-arrhythmic and may lead to drug-induced long QT syndrome-LQTS. There are a number of natural strategies for rational drug design; one dubbed the “passive” approach avoids block of hERG1 whereas the “proactive” strategy designs treatments to activate the channel. While “passive” approach has been developed for decades, studies of structural mechanisms of hERG channel activation by small molecules are truly novel. Accordingly, design of the hERG openers or current activators may offer a momentum for modern anti-arrhythmia drug development. Significant number of small molecules with capacity for hERG activation was identified in mandatory hERG screens. To establish possible correlation between activators structure and reactivity, we attempted to construct a universal pharmacophore model for hERG channel openers using PHASE protocol. The biochemical data on 38 K+ channel activators are used in training and test sets. These compounds span a wide range of structurally different chemotypes with ∼10∧5-fold variances in binding affinity, which is sufficient for statistically sound model. A developed five sites AAHHR (A, hydrogen-bond accepting, H, hydrophobic, R, aromatic) pharmacophore model has showed reasonable high statistical results compared to other constructed models and was selected for steric and electrostatic contour maps analysis. The predictive power of the model was also tested with 6 external test-set (as true unknowns) compounds. Pharmacophore model is also combined with previously developed receptor-based homology model of hERG K channel and novel activators are generated and screened. The developed ligand-based models may serve as a basis for the synthesis of novel potential therapeutic hERG activators.