Quantum Mechanics Modeling of Oxetanes as Epoxide Hydrolase Substrates

Abstract

Background: Epoxide hydrolases comprise an important class of enzymes that have critical functions in the detoxification of xenobiotics and regulation of signaling molecules. In addition to epoxides, oxetanes have recently been identified as novel substrates of microsomal epoxide hydrolase (mEH). Oxetanes are common scaffolds used in medicinal chemistry design to improve potency and drug-like properties. Metabolism of oxetanes by mEH can result in high uncertainties in the prediction of human clearance due to extrahepatic contribution and large interindividual variability. Therefore, reducing mEH-mediated oxetane metabolism is highly desirable to minimize its contribution to clearance. Objective: The aim of the study is to evaluate whether quantum mechanical parameters are able to predict the hydrolytic rate of mEH-mediated oxetane metabolism in order to guide medicinal chemistry design in order to minimize mEH contribution to clearance. Methods: Quantum mechanics modeling was used to evaluate the hydrolytic rate of twenty-three oxetanes by mEH. All modeling studies were performed with the Maestro software package. Results: The results show that LUMO energy is highly correlated with the diol formation rate of oxetane hydrolysis by mEH for compounds that are structurally similar, while other quantum mechanical parameters are less predictive. The data suggest that the intrinsic reactivity determines the hydrolytic rate of oxetanes. This occurs when the orientations of the molecules in the mEH active site are similar. Predictions of mEH substrate metabolic rates using LUMO are most accurate when comparing subtle structural changes without drastic changes in MW and chemotype. Conclusion: The study suggests that LUMO energy can be used to rank-order oxetanes for their hydrolytic rate by mEH for structurally similar compounds. This finding enables the medicinal chemistry design to reduce mEH-mediated oxetane metabolism based on the calculated LUMO energy.