title: A k-nearest neighbor classification of hERG K(+) channel blockers.
abstract: A series of 172 molecular structures that block the hERG K(+) channel were used to develop a classification model where, initially, eight types of PaDEL fingerprints were used for k-nearest neighbor model development. A consensus model constructed using Extended-CDK, PubChem and Substructure count fingerprint-based models was found to be a robust predictor of hERG activity. This consensus model demonstrated sensitivity and specificity values of 0.78 and 0.61 for the internal dataset compounds and 0.63 and 0.54 for the external (PubChem) dataset compounds, respectively. This model has identified the highest number of true positives (i.e. 140) from the PubChem dataset so far, as compared to other published models, and can potentially serve as a basis for the prediction of hERG active compounds. Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.
authors: Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden. swapnil.chavan@lnu.se.
authors: Swapnil
authors: S
authors: Chavan
authors: eADMET GmbH, Lichtenbergstraße 8, 85748, Garching, Munich, Germany.
authors: Ahmed
authors: A
authors: Abdelaziz
authors: Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden.
authors: Jesper G
authors: JG
authors: Wiklander
authors: Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden. ian.nicholls@lnu.se.|Department of Chemistry-BMC, Uppsala University, Box 576, 751 23, Uppsala, Sweden. ian.nicholls@lnu.se.
authors: Ian A
authors: http://orcid.org/0000-0002-0407-6542
authors: IA
authors: Nicholls
mesh_terms: D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D012984:Software
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D054852:Small Molecule Libraries
keywords: Classification model; Ikr; KCNH2; Toxicity; hERG blockers; k-nearest neighbor (k-NN)