in silico Prediction of Regioselectivity in Cytochrome P450 Mediated Metabolism

다국어 초록 (Multilingual Abstract)

Cytochrome P450s are involved in the metabolism of a wide variety of xenobiotic chemicals. 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 cytochrome P450 3A4, 2C9, and 2D6 mediated metabolism. In the model, the ensemble catalyticphore-based docking method was implemented for the accessibility prediction and the reactivity estimation method and ATDL descriptor were used for the reactivity prediction.Diverse CYP2C9, 2D6, and 3A4 substrates were used in the prediction of regioselectivity, aliphatic hydroxylation, N-dealkylation, O-dealkylation, aromatic hydroxylation, and electron transfer reaction. The metabolic reaction informations were collected for 296 CYP3A4 substrates, 98 CYP2C9 substrates and 129 CYP2D6 substrates from public literatures. All data were divided as training set and validation set for the ensemble catalyticphore-based docking method. MLite predicted correctly about 74.7%, 96.0%, and 85.3% of the first three sites in the ranking list on the validation set of CYP3A4, CYP2C9, and CYP2D6, respectively. This predictability is comparable with that of another combined model, MetaSite, and recently published QSAR model proposed by Sheridan et al. MLite also offer information about binding configurations of substrate-enzyme complex. This may be useful in drug modification by the structure-based drug design.