Molecular details of prostaglandin synthesis catalyzed by cyclooxygenase-2 and its inhibition by aspirin

Resumo

Cyclooxygenase-2 (COX-2) is a membrane-associated homodimeric bifunctional hemoprotein enzyme that catalyzes the oxygenation of several PUFAs. COX-2 is one of the two main human enzymes responsible for inflammation processes. Therefore, COX-2 transforms AA to lipid pro-inflammatory mediators, such as prostaglandins. This production is associated with many human pathologies, including inflammation, cardiovascular diseases and cancer. In this sense, COX-2 is considered an important pharmacological target of the nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and diclofenac, producing the well-known analgesic, antipyretic, and anti-inflammatory effects. Besides, COX-2 also participates in the biosynthesis of lipid pro-resolving mediators, such as resolvins, through its interaction with EPA. However, most of the molecular details of the synthesis of prostaglandins within the COX-2: AA and COX-2: EPA Michaelis complexes remain unknown, as well as their inhibition within COX-2: AA by aspirin. For that reason, in this thesis, MD simulations and the QM/MM method have been combined for a better understanding of such molecular insights.