QSTR with extended topochemical atom (ETA) indices. 13. Modelling of hERG K+channel blocking activity of diverse functional drugs using different chemometric tools
Kunal Roy, Gopinath Ghosh · Molecular Simulation · 2009
To accelerate the drug discovery process, early prediction of human ether a-go-go (hERG) K+ channel affinity of drug candidates is becoming an important aspect. We have therefore developed quantitative structure–toxicity relationship models with extended topochemical atom (ETA) indices for hERG K+ channel blocking activity of diverse functional drugs using different chemometric tools like factor analysis followed by multiple linear regression (FA-MLR), stepwise regression and partial least squares. The data set was divided into a training set of 50 compounds and a test set of 17 compounds based on K-means clustering technique. The ETA models were compared with those developed with a pool of other topological indices. Finally, an attempt was made to develop models from the combined pool of topological (ETA and non-ETA) descriptors. It was found that on using ETA parameters along with non-ETA ones, there was a considerable increase in the quality of the models. The best model came from stepwise regression using a combined set of descriptors (Q 2 = 0.546, = 0.619). The ETA model suggests that hERG channel blocking increases with the increase of molecular bulk and electron richness and decreases with the increase of functionalities of the carboxylic acid group and the aliphatic tertiary nitrogen fragment.