A Pharmacophore Modeling Study of Drugs Inducing Cardiotoxic Side Effects

• 来源期刊: 中国化学（英文版）
• 年，卷（期）: 2008,（11）
• 页码范围: 2125-2132
• 页数: 8页
• 语种: 英文

摘要

The blockade of human ether-a-go-go related gene(hERG)potassium channel is one of the major critical factors associated with QT interval prolongation and will induce arrhythmia called torsades de pointes(TdP).To evaluate the potent cardiotoxic effect of drug candidates,a three-dimensional cardiotoxic model was developed from hERG blockers.The chemically distinct compounds with either antiarrhythmic potency or potential cardiotoxic effect attributed to the inhibition of hERG were included in both the training set and test set of this model.By using HypoGen module in Catalyst program,the best hypothesis(Hypol),consisting of four features:one positive ionizable feature,two aromatic rings and one hydrophobic group,was obtained with the best correlation coefficient of 0.929,a lowest rms deviation of 1.139,and the highest cost difference of 58.307.It was then validated by a test set consisting of 24 compounds and by a cross-validation of 95% confidence level through randomizing the data by using CatScramble module,which suggested that a predictive cardiotoxic model had been successfully obtained and would be very helpful in understanding the blockade mechanism of hERG potassium channel and providing insights into avoiding unnecessary cardiotoxic effect on drug development.