Computational Investigation of the Binding Interactions of Paracetamol, Ibuprofen, and Their Complexes With Cyclooxygenase Enzymes

The combination of paracetamol and ibuprofen is widely used in clinical practice for the management of acute pain and fever. Paracetamol exerts its analgesic and antipyretic effects primarily through central mechanisms, whereas ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), acts by inhibiting cyclooxygenase enzymes and reducing prostaglandin synthesis. The concurrent administration of these agents provides complementary mechanisms of action, resulting in enhanced analgesic efficacy compared with either drug alone. Numerous clinical studies have demonstrated that this combination is effective in postoperative pain, musculoskeletal disorders, and febrile conditions. This multimodal approach can enhance therapeutic efficacy while allowing lower doses of each medication. When administered appropriately, the combination is generally well tolerated and has a favorable safety profile. The primary aim of this study was to investigate whether the interactions of paracetamol and ibuprofen with cyclooxygenase (COX) enzymes are affected when the two drugs are administered in combination. Molecular docking simulations were performed using the HEX 8.0 docking software, with binding energy serving as an indicator of interaction strength and complex stability. The results demonstrated that the ibuprofen–paracetamol complex exhibited the strongest affinity for COX-2, with a binding energy of –290.80 kcal/mol. This finding suggests that, when ibuprofen functions as the receptor and paracetamol as the ligand, the resulting complex achieves the most favorable accommodation within the COX-2 binding site. These observations underscore the significance of evaluating drug–drug interactions at the molecular level, as such interactions may influence therapeutic outcomes. Consequently, a comprehensive understanding of these mechanisms is essential for optimizing the efficacy and safety of combination therapies.