Computational determination of hERG-related cardiotoxicity of drug candidates.

BACKGROUND: Drug candidates often cause an unwanted blockage of the potassium ion channel of the human ether-a-go-go-related gene (hERG). The blockage leads to long QT syndrome (LQTS), which is a severe life-threatening cardiac side effect. Therefore, a virtual screening method to predict drug-induced hERG-related cardiotoxicity could facilitate drug discovery by filtering out toxic drug candidates. RESULT: In this study, we generated a reliable hERG-related cardiotoxicity dataset composed of 2130 compounds, which were carried out under constant conditions. Based on our dataset, we developed a computational hERG-related cardiotoxicity prediction model. The neural network model achieved an area under the receiver operating characteristic curve (AUC) of 0.764, with an accuracy of 90.1%, a Matthews correlation coefficient (MCC) of 0.368, a sensitivity of 0.321, and a specificity of 0.967, when ten-fold cross-validation was performed. The model was further evaluated using ten drug compounds tested on guinea pigs and showed an accuracy of 80.0%, an MCC of 0.655, a sensitivity of 0.600, and a specificity of 1.000, which were better than the performances of existing hERG-toxicity prediction models. CONCLUSION: The neural network model can predict hERG-related cardiotoxicity of chemical compounds with a high accuracy. Therefore, the model can be applied to virtual high-throughput screening for drug candidates that do not cause cardiotoxicity. The prediction tool is available as a web-tool at http://ssbio.cau.ac.kr/CardPred .

In silico approaches and tools for the prediction of drug metabolism and fate: A review.

The fate of administered drugs is largely influenced by their metabolism. For example, endogenous enzyme-catalyzed conversion of drugs may result in therapeutic inactivation or activation or may transform the drugs into toxic chemical compounds. This highlights the importance of drug metabolism in drug discovery and development, and accounts for the wide variety of experimental technologies that provide insights into the fate of drugs. In view of the high cost of traditional drug development, a number of computational approaches have been developed for predicting the metabolic fate of drug candidates, allowing for screening of large numbers of chemical compounds and then identifying a small number of promising candidates. In this review, we introduce in silico approaches and tools that have been developed to predict drug metabolism and fate, and assess their potential to facilitate the virtual discovery of promising drug candidates. We also provide a brief description of various recent models for predicting different aspects of enzyme-drug reactions and provide a list of recent in silico tools used for drug metabolism prediction.