Oh Won Seok, Kim Doo Nam, Jung Jihoon, Cho Kwang-Hwi, No Kyoung Tai
Department of Biotechnology, Yonsei University, Seoul 120-749, Korea.
J Chem Inf Model. 2008 Mar;48(3):591-601. doi: 10.1021/ci7003576. Epub 2008 Feb 22.
Cytochrome P450 3A4 metabolizes nearly 50% of the drugs currently in clinical use with a broad range of substrate specificity. Early prediction of metabolites of xenobiotic compounds is crucial for cost efficient drug discovery and development. We developed a new combined model, MLite, for the prediction of regioselectivity in the cytochrome P450 3A4 mediated metabolism. In the model, the ensemble catalyticphore- based docking method was implemented for the accessibility prediction, and the activation energy estimation method of Korzekwa et al. was used for the reactivity prediction. Four major metabolic reactions, aliphatic hydroxylation, N-dealkylation, O-dealkylation, and aromatic hydroxylation reaction, were included and the reaction data, metabolite information, were collected for 72 well-known substrates. The 47 drug molecules were used as the training set, and the 25 well-known substrates were used as the test set for the ensemble catalyticphore-based docking method. MLite predicted correctly about 76% of the first two sites in the ranking list of the test set. This predictability is comparable with that of another combined model, MetaSite, and the recently published QSAR model proposed by Sheridan et al. MLite also offers information about binding configurations of the substrate-enzyme complex. This may be useful in drug modification by the structure-based drug design.
细胞色素P450 3A4代谢目前临床使用的近50%的药物，具有广泛的底物特异性。对外源化合物代谢物的早期预测对于经济高效的药物发现和开发至关重要。我们开发了一种新的组合模型MLite，用于预测细胞色素P450 3A4介导的代谢中的区域选择性。在该模型中，基于催化基团的整体对接方法用于可及性预测，Korzekwa等人的活化能估计方法用于反应性预测。纳入了四种主要代谢反应，即脂肪族羟基化、N-脱烷基化、O-脱烷基化和芳香族羟基化反应，并收集了72种知名底物的反应数据即代谢物信息。47个药物分子用作训练集，25种知名底物用作基于催化基团整体对接方法的测试集。MLite在前两位预测位点中正确预测了测试集排名列表中约76%的位点。这种可预测性与另一种组合模型MetaSite以及Sheridan等人最近发表的QSAR模型相当。MLite还提供了底物-酶复合物结合构型的信息。这在基于结构的药物设计进行药物修饰中可能有用。
