title: Prediction of hERG Liability - Using SVM Classification, Bootstrapping and Jackknifing.
abstract: Drug-induced QT prolongation leads to life-threatening cardiotoxicity, mostly through blockage of the human ether-à-go-go-related gene (hERG) encoded potassium ion (K+) channels. The hERG channel is one of the most important antitargets to be addressed in the early stage of drug discovery process, in order to avoid more costly failures in the development phase. Using a thallium flux assay, 4,323 molecules were screened for hERG channel inhibition in a quantitative high throughput screening (qHTS) format. Here, we present support vector classification (SVC) models of hERG channel inhibition with the averaged area under the receiver operator characteristics curve (AUC-ROC) of 0.93 for the tested compounds. Both Jackknifing and bootstrapping have been employed to rebalance the heavily biased training datasets, and the impact of these two under-sampling rebalance methods on the performance of the predictive models is discussed. Our results indicated that the rebalancing techniques did not enhance the predictive power of the resulting models; instead, adoption of optimal cutoffs could restore the desirable balance of sensitivity and specificity of the binary classifiers. In an external validation set of 66 drug molecules, the SVC model exhibited an AUC-ROC of 0.86, further demonstrating the utility of this modeling approach to predict hERG liabilities.
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sampada
authors.initials: S
authors.lastname: Shahane
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D060388:Support Vector Machine
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations
keywords: ROC; bootstrap; hERG; jackknife; rebalance; support vector classification