Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: Insights from docking, molecular dynamics, and quantum chemical calculations

A combination of quantum chemical calculations and molecular simulations (D OCKing and molecular dynamics) is used to investigate the metabolism of sir olimus (rapamycin) and its derivative everolimus (SDZ-RAD) by cytochrome P4 50 3A4. Both molecules are drugs with high immunosuppressive activity. Our calculations yield qualitative predictions of the regio-specificities of th e hydroxylations and O-dealkylations occurring in these two substrates whic h are in good agreement with recent experimental results. An analysis of th e modeled enzyme-substrate interactions allows us to rationalize the reduce d metabolic activity of the larger substrate everolimus compared to sirolim us. Moreover, our simulations suggest that hydrogen donor functionalities c lose to the metabolic site are important for anchoring the substrate at the active center of the enzyme. In particular, we predict that replacing one hydroxyl group by a fluorine atom should considerably suppress the major me tabolic reaction in sirolimus, 39-O-demethylation.