metabolicomp · Computational dynamics studies of drug metabolism by P450 enzymes

Computational dynamics studies of drug metabolism by P450 enzymes

Iron-containing enzymes, such as the cytochrome P450s (mainly found in livers), play key roles in the metabolism of drugs and small-molecules in human body, and also in biotechnology as they have shown efficiency and specificity in substrate functionalization. Understanding metabolism and drug-drug interactions is crucial in the development of safe and efficacious pharmaceutical agents. For instance, ethylcarbamate reacting with P450 mainly results in hydroxylation product; however, in the competing pathway of desaturation, it could lead to an alkene product, which can serve as precursor to epoxide, a carcinogen. Due to the difficulty in capturing reactive intermediates, recent computational developments have helped fill in a more complete picture of P450’s activities and selectivity, focusing on the importance of their various spin states in catalytic roles. Basic mechanisms of desaturation and hydroxylation of ethylcarbamate by P450 model active site have been studied computationally; however, non-statistical dynamics had not been explored. After elucidating the stationary points along the PES, we carried out dynamics study with ethylcarbamate substrate to examine how the flat potential energy surfaces following C-H abstraction may play a role in product distributions. The aims of the project are to develop an understanding for alcohol/alkene product selectivity for ethylcarbamate using quasi-classical dynamics simulations, and to also understand the difference between heme and non-heme Fe-containing active site in product selectivity. In an extended effort to study reactive intermediates and natural metabolites, we collaborated with Burton group in Oxford to study oxonium ions and their roles in natural product biosyntheses.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз