Support vector machines classification of hERG liabilities based on atom types.

Article Details

Citation

Jia L, Sun H

Support vector machines classification of hERG liabilities based on atom types.

Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16.

PubMed ID
18448342 [ View in PubMed
]
Abstract

Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AmiodaroneHERG human cardiac K+ channelIC 50 (nM)10000N/AN/ADetails
AstemizolePotassium voltage-gated channel subfamily H member 2IC 50 (nM)10N/AN/ADetails
AzimilidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)1412.54N/AN/ADetails
BepridilPotassium voltage-gated channel subfamily H member 2IC 50 (nM)549.54N/AN/ADetails
CarvedilolPotassium voltage-gated channel subfamily H member 2IC 50 (nM)10471.29N/AN/ADetails
ChlorpromazinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)1479.11N/AN/ADetails
CisapridePotassium voltage-gated channel subfamily H member 2IC 50 (nM)39.81N/AN/ADetails
ClarithromycinPotassium voltage-gated channel subfamily H member 2IC 50 (nM)58884.37N/AN/ADetails
DisopyramidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)91201.08N/AN/ADetails
DofetilidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)10N/AN/ADetails
FlecainidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)3890.45N/AN/ADetails
FluoxetinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)1513.56N/AN/ADetails
HalofantrinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)200N/AN/ADetails
IbutilidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)10N/AN/ADetails
ImipraminePotassium voltage-gated channel subfamily H member 2IC 50 (nM)3388.44N/AN/ADetails
LoratadinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)169.82N/AN/ADetails
PerhexilinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)7762.47N/AN/ADetails
PimozidePotassium voltage-gated channel subfamily H member 2IC 50 (nM)50.12N/AN/ADetails
SertindolePotassium voltage-gated channel subfamily H member 2IC 50 (nM)10N/AN/ADetails
TerfenadinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)200N/AN/ADetails
ThioridazinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)363.08N/AN/ADetails