New Combined Model for the Prediction of Regioselectivity in Cytochrome P450/3A4 Mediated Metabolism

Abstract

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.

Quantitative Prediction of Regioselectivity Toward Cytochrome P450/3A4 Using Machine Learning Approaches

“…According to reaction types, values of activation energies were empirically assessed in the literatures. The values of activation energy for aliphatic oxidation (1)(2)(3)(4)(5) are cited from Reference, [13] and those of aromatic oxidation (6 and 7) are cited from Reference. [14] Fukui functions are derivatives of the electron density in terms of the number of electrons.…”

“…These features make it difficult to predict the regioselectivity of CYP 3A4. Until now, several regioselectivity predictions using quantum chemistry have been investigated by Olsen for CYP 1A2 and by Singh, [2] Oh, [5] and Kim [9] for CYP 3A4. In particuAbstract: In the drug discovery process, it is important to know the properties of both drug candidates and their metabolites.…”

Computer-based substrate specifity prediction for cytochrome P450

“…задан разными способами: использовать параллельно известную структуру белка или его компьютерную модель (как в случае [26]), задать максимальные размеры лигандов или на основе этих же структур лигандов построить модель псевдорецептора [30]. Таким образом, построенная на основе репрезентативного набора субстратов фармакофорная модель должна отражать основные особенности в структуре лигандов и позволяет обоснованно предполагать какие функциональные группировки в активном центре фермента должны участвовать в связывании.…”

“…Для ряда цитохромов Р450 (2С9, 2D6, 3A4) были построены фармакофорные модели на основе наборов субстратов и ингибиторов [24][25][26]. Так для цитохрома 2С9 первоначальная фармакофорная модель субстратов включала только одну фармакофорную точку, анионную группировку, расположенную на расстоянии 7 ангстрем от места гидроксилирования [27].…”

Improvement of Site of Metabolism Predictions for CYP3A4 by Using Discriminant Analysis of Compound Preference of CYP3A4 X‐Ray Structural Conformers and Subsequent Docking

“…In order to account for conformational freedom available to the CYP3A4 the prediction of the site of metabolism using docking has been developed using two different structures as starting points [5,6].…”