Exploring molecular docking with MM-GBSA and molecular dynamics simulation to predict potent inhibitors of cyclooxygenase (COX-2) enzyme from terpenoid-based active principles of <i>Zingiber</i> species

Cyclooxygenase 2 (COX-2), the key enzyme involved in prostaglandin (PGs) production, is known to take part in inflammatory and immune responses. Though COX-2 inhibitors are therapeutically effective anti-inflammatory drugs, they deficit anti-thrombotic activity thus leading to increased cardiovascular diseases. Therefore, COX-2 inhibitors with improved therapeutic efficacy and tolerance are still needed. In recent years, traditional medicine systems have paid attention to the essential oil of genus <i>Zingiber</i>, particularly for the treatment of various inflammatory illnesses, with lesser side effects. Thus, the present study aims to explore the anti-inflammatory activity of <i>Zingiber</i> essential oil through computational-biology approaches. In this regard, virtual screening, molecular docking, and simulations were carried out on 53 compounds derived from the essential oil of <i>Zingiber</i> species in order to provide mechanistic insights into COX-2 inhibition and identify the most actively potent anti-inflammatory compounds. Among all the docked ligands, epi-cubenol, δ-cadinene, γ-eudesmol, cubenol, and α-terpineol were found to be powerful bioactive compounds with an increased binding affinity towards COX-2 along with favorable physiochemical properties. Additionally, MD simulation in DPPC lipid bilayers was studied to examine the intrinsic dynamics and adaptability of the chosen ligands and COX-2-complexes. The findings showed that the selected five components interacted steadily with the COX-2 active site residues throughout the simulation via different bondings. The integrative-computational approach showed that the identified natural compounds may be taken into further consideration for potential <i>in vitro</i> and <i>in vivo</i> evaluation as COX-2 inhibitors, which would lead to the development of more potent and efficient anti-inflammatory drugs. Communicated by Ramaswamy H. Sarma