PreMetabo: An in silico phase I and II drug metabolism prediction platform.

This study aimed to develop a drug metabolism prediction platform using knowledge-based prediction models. Site of Metabolism (SOM) prediction models for four cytochrome P450 (CYP) subtypes were developed along with uridine 5'-diphosphoglucuronosyltransferase (UGT) and sulfotransferase (SULT) substrate classification models. The SOM substrate for a certain CYP was determined using the sum of the activation energy required for the reaction at the reaction site of the substrate and the binding energy of the substrate to the CYP enzyme. Activation energy was calculated using the EaMEAD model and binding energy was calculated by docking simulation. Phase II prediction models were developed to predict whether a molecule is the substrate of a certain phase II conjugate protein, i.e., UGT or SULT. Using SOM prediction models, the predictability of the major metabolite in the top-3 was obtained as 72.5-84.5% for four CYPs, respectively. For internal validation, the accuracy of the UGT and SULT substrate classification model was obtained as 93.94% and 80.68%, respectively. Additionally, for external validation, the accuracy of the UGT substrate classification model was obtained as 81% in the case of 11 FDA-approved drugs. PreMetabo is implemented in a web environment and is available at https://premetabo.bmdrc.kr/.

Regioselective C-H hydroxylation of omeprazole sulfide by Bacillus megaterium CYP102A1 to produce a human metabolite.

OBJECTIVES: To find a simple enzymatic strategy for the efficient synthesis of the expensive 5'-hydroxyomeprazole sulfide, a recently identified minor human metabolite, from omeprazole sulfide, which is an inexpensive substrate. RESULTS: The practical synthetic strategy for the 5'-OH omeprazole sulfide was accomplished with a set of highly active CYP102A1 mutants, which were obtained by blue colony screening from CYP102A1 libraries with a high conversion yield. The mutant and even the wild-type enzyme of CYP102A1 catalyzed the high regioselective (98 %) C-H hydroxylation of omeprazole sulfide to 5'-OH omeprazole sulfide with a high conversion yield (85-90 %). CONCLUSIONS: A highly efficient synthesis of 5'-OH omeprazole sulfide was developed using CYP102A1 from Bacillus megaterium as a biocatalyst.