We present a study based on density functional theory calculations to explore the rate limiting steps of product formation for oxidation by Flavin-containing Monooxygenase (FMO) and glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes. FMOs are responsible for the modification phase of metabolism of a wide diversity of drugs, working in conjunction with Cytochrome P450 (CYP) family of enzymes, and UGTs are the most important class of drug conjugation enzymes. Reactivity calculations are important for prediction of metabolism by CYPs and reactivity alone explains around 70–85% of the experimentally observed sites of metabolism within CYP substrates. In the current work we extend this approach to propose model systems which can be used to calculate the activation energies, i.e. reactivity, for the rate-limiting steps for both FMO oxidation and glucuronidation of potential sites of metabolism. These results are validated by comparison with the experimentally observed reaction rates and sites of metabolism, indicating that the presented models are suitable to provide the basis of a reactivity component within generalizable models to predict either FMO or UGT metabolism.

我们提出了一项基于密度泛函理论计算的研究，以探索含黄素单加氧酶 (FMO) 的氧化产物形成和 UDP-葡萄糖醛酸转移酶 (UGT) 家族酶的葡萄糖醛酸化的限速步骤。FMO 负责多种药物代谢的修饰阶段，与细胞色素 P450 (CYP) 酶家族一起工作，而 UGT 是最重要的一类药物结合酶。反应性计算对于预测 CYP 的代谢很重要，仅反应性就可以解释 CYP 底物中约 70-85% 的实验观察到的代谢位点。在目前的工作中，我们扩展了这种方法以提出可用于计算活化能的模型系统，即反应性，用于潜在代谢部位的 FMO 氧化和葡萄糖醛酸化的限速步骤。这些结果通过与实验观察到的反应速率和代谢位点的比较得到验证，表明所提出的模型适合提供可推广模型中反应性成分的基础，以预测 FMO 或 UGT 代谢。