Quantitative Structure−Activity Relationship Studies on Inhibition of HERG Potassium Channels

Abstract

The human ether-a-go-go-related gene (HERG) protein forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, I(Kr), and its blockade is a significant contributor to prolongation of the QT interval. Using descriptors which have clear physicochemical meanings and are familiar to medicinal chemists, we have carried out 2D-quantitative structure-activity relationship (2D-QSAR) studies on 104 HERG channel blockers with diverse structures collected from the literature, and we have formulated interpretable models to guide chemical-modification studies and virtual screening. Statistically significant descriptors were selected by a genetic algorithm, and the final model included the octanol/water partition coefficient, topological polar surface area, diameter, summed surface area of atoms with partial charges from -0.25 to -0.20, and an indicator variable representing the experimental conditions. The statistics were r = 0.839, r2 = 0.704, q2 = 0.671, s = 0.763, and F = 46.6. The correspondence of the molecular determinants derived from the 2D-QSAR models with the 3D structural characteristics of the putative binding site in a homology-modeled HERG channel is also discussed.