Prediction of human cytochrome P450 2B6‐substrate interactions using hierarchical support vector regression approach

The human cytochrome P450 2B6 can metabolize a number of clinical drugs. Inhibition of CYP2B6 by coadministered multiple drugs may lead to drug–drug interactions and undesired drug toxicity. The aim of this investigation is to develop an in silico model to predict the interactions between P450 2B6 and novel inhibitors using a novel hierarchical support vector regression (HSVR) approach, which simultaneously takes into account the coverage of applicability domain (AD) and the level of predictivity. Thirty‐seven molecules were deliberately selected and rigorously scrutinized from the literature data, of which 26 and 11 molecules were treated as the training set and the test set to generate the models and to validate the generated models, respectively. The generated HSVR model gave rise to an r² value of 0.97 for observed versus predicted pK_m values for the training set, a q² value of 0.93 by the 10‐fold cross‐validation, and an r² value of 0.82 for the test set. Additionally, the predicted results show that the HSVR model outperformed the individual local models, the global model, and the consensus model. Thus, this HSVR model provides an accurate tool for the prediction of human cytochrome P450 2B6‐substrate interactions and can be utilized as a primary filter to eliminate the potential selective inhibitor of CYP2B6. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009