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Quantitative structure - Activity relationship studies on inhibition of HERG potassium channels

Journal of Chemical Information and Modeling, ISSN: 1549-960X, Vol: 46, Issue: 3, Page: 1371-1378
2006
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Review Description

The human ether-a-go-go-related gene (HERG) protein forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, IKF, 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, r = 0.704, q = 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. © 2006 American Chemical Society.

Bibliographic Details

Yoshida, Katsumi; Niwa, Tomoko

American Chemical Society (ACS)

Chemistry; Chemical Engineering; Computer Science; Social Sciences

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