title: QSAR modeling and data mining link Torsades de Pointes risk to the interplay of extent of metabolism, active transport, and HERG liability.
abstract: We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability of the best models to predict the activity of 26 proprietary compounds tested in radioligand binding displacement (RBD). Results proved the necessity to use multiple validation sets for a true estimation of model accuracy and demonstrated that using various descriptors and algorithms improves the performance of ligand-based models. Intriguingly, one of the most accurate models uncovered an unexpected link between extent of metabolism and hERG liability. This hypothesis was fairly reinforced by using the Biopharmaceutics Drug Disposition Classification System (BDDCS) that recognized 94% of the hERG inhibitors as extensively metabolized in vivo. Data mining suggested that high Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition, extent of metabolism, active transport, and possibly solubility. Overall, these new findings might improve both the decision making skills of pharmaceutical scientists to mitigate hERG liability during the drug discovery process and the TdP risk assessment during drug development.
authors: Laboratory for Chemometrics and Cheminformatics, Chemistry Department, University of Perugia, Via Elce di Sotto 10, I-06123 Perugia, Italy.
authors: Fabio
authors: F
authors: Broccatelli
authors: Raimund
authors: R
authors: Mannhold
authors: Alessio
authors: A
authors: Moriconi
authors: Sandra
authors: S
authors: Giuli
authors: Emanuele
authors: E
authors: Carosati
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D016171:Torsades de Pointes
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human