QSTR with extended topochemical atom (ETA) indices. 13. Modelling of hERG K+ channel blocking activity of diverse functional drugs using different chemometric tools

摘要

To accelerate the drug discovery process, early prediction of human ether a-go-go (hERG) K~+channel affinity of drugcandidates is becoming an important aspect. We have therefore developed quantitative structure–toxicity relationshipmodels with extended topochemical atom (ETA) indices for hERG K~+channel blocking activity of diverse functional drugsusing different chemometric tools like factor analysis followed by multiple linear regression (FA-MLR), stepwise regressionand partial least squares. The data set was divided into a training set of 50 compounds and a test set of 17 compounds basedon K-means clustering technique. The ETA models were compared with those developed with a pool of other topologicalindices. 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 thequality of the models. The best model came from stepwise regression using a combined set of descriptors (Q ~2=0.546,R~2=0.619). TheETA model suggests that hERG channel blocking increases with the increase of molecular bulk pred and electron richness and decreases with the increase of functionalities of the carboxylic acid group and the aliphatic tertiarynitrogen fragment.