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

The human ether-a-go-go-related gene (HERG) protein forms the ion channel responsible for the rapidly
acting delayed rectifier potassium current, IKr, 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.