title: ADMET evaluation in drug discovery. 12. Development of binary classification models for prediction of hERG potassium channel blockage.
abstract: Inhibition of the human ether-a-go-go related gene (hERG) potassium channel may result in QT interval prolongation, which causes severe cardiac side effects and is a major problem in clinical studies of drug candidates. The development of in silico tools to filter out potential hERG potassium channel blockers in early stages of the drug discovery process is of considerable interest. Here, a diverse set of 806 compounds with hERG inhibition data was assembled, and the binary hERG classification models using naive Bayesian classification and recursive partitioning (RP) techniques were established and evaluated. The naive Bayesian classifier based on molecular properties and the ECFP_8 fingerprints yielded 84.8% accuracy for the training set using the leave-one-out (LOO) cross-validation procedure and 85% accuracy for the test set of 120 molecules. For the two additional test sets, the model achieved 89.4% accuracy for the WOMBAT-PK test set, and 86.1% accuracy for the PubChem test set. The naive Bayesian classifiers gave better predictions than the RP classifiers. Moreover, the Bayesian classifier, employing molecular fingerprints, highlights the important structural fragments favorable or unfavorable for hERG potassium channel blockage, which offers extra valuable information for the design of compounds avoiding undesirable hERG activity.
authors.affiliation: Institute of Functional Nano & Soft Materials-FUNSOM and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Sichao
authors.initials: S
authors.lastname: Wang
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Liling
authors.initials: L
authors.lastname: Zhang
authors.forename: Huidong
authors.initials: H
authors.lastname: Yu
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
mesh_terms: D001499:Bayes Theorem; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers