3D-SDAR modeling of hERG potassium channel affinity: A case study in model design and toxicophore identification.

A dataset of 237 human Ether-à-go-go Related Gene (hERG) potassium channel inhibitors (180 of which were used for model building and validation, whereas 57 constituted the "true" external prediction set) collected from 22 literature sources was modeled by 3D-SDAR. To produce reliable and reproducible classification models for hERG blocking, the initial set of 180 chemicals was split into two subsets: a balanced modeling set consisting of 118 compounds and an unbalanced validation set comprised of 62 compounds. A PLS bagging-like algorithm written in Matlab was used to process the data and assign each compound to one of the two (hERG+ or hERG-) activity classes. The best predictive model evaluated on the basis of a fully randomized hold-out test set (comprising 20% of the modeling set) used 4 latent variables and a grid of 6ppm×6ppm×1Å in the C-C region, 6ppm×30ppm×1Å in the C-N region, and 30ppm×30ppm×1Å in the N-N region. An overall accuracy of 0.84 was obtained for both the hold-out test set and the validation set. Further, an external prediction set consisting of 57 drugs and drug derivatives was used to estimate the true predictive power of the reported 3D-SDAR model - a slight reduction of the overall accuracy down to 0.77 was observed. 3D-SDAR map of the most frequently occurring bins and their projection on the standard coordinate space of the chemical structures allowed identification of a three-center toxicophore composed of two aromatic rings and an amino group. A U test along the distance axis of the most frequently occurring 3D-SDAR bins was used to set the distance limits of the toxicophore. This toxicophore was found to be similar to an earlier reported phospholipidosis (PLD) toxicophore.