title: Prediction of hERG K+ blocking potency: application of structural knowledge.
abstract: Modelling of QT-prolongation has been performed using data for 19 structurally diverse hERG K+ channel blocking drugs taken from literature. The modelling used hydrophobicity corrected for ionisation (log D) and various 2D and 3D physico-chemical molecular descriptors. Stepwise regression produced a two parameter, interpretable and transparent QSAR with good statistical fit, including log D and the maximum diameter of molecules (Dmax). Two strategies were applied for model validation: (i) a scrambling procedure, i.e., training the total set of 19 chemicals after randomising the hERG K+ channel blocking activity data and (ii) use of external validation sets. Validation of the models showed them to be stable and statistically significant. The effect of molecular size on QT-prolongation side effect is discussed.
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool L3 3AF, UK.
authors.forename: A O
authors.initials: AO
authors.lastname: Aptula
authors.forename: M T D
authors.initials: MT
authors.lastname: Cronin
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D019359:Knowledge; D008954:Models, Biological; D008968:Molecular Conformation; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis
chemical_list: D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated