ABSTRACT
BACKGROUND: Cyclooxygenase-2 (COX-2) is an important enzyme with numerous biological functions. Overexpression of COX-2 has been associated with various inflammatory-related diseases and therefore, projected as an important pharmacological target. PURPOSE: We aimed to investigate the inhibitory potential of isolated bioactive compounds, 3-caffeoyl-4-dihydrocaffeoyl quinic acid (CDQ) and isorhamnetin 3-O-ß-d-glucopyranoside (IDG), from Salicornia herbacea against COX-2 using both computational and in vitro approaches. METHODS: Computational analysis, including molecular docking, molecular dynamics (MD) simulations, and post-simulations analysis, were employed to estimate the binding affinity and stability of CDQ and IDG in the catalytic pocket of COX-2 against Celecoxib as positive control. These predictions were further evaluated using in vitro enzyme inhibition as well as gene expression mediation in macrophages cells. RESULTS: Molecular docking analysis revealed substantial binding energy of CDQ (-6.1 kcal/mol) and IDG (-5.9 kcal/mol) with COX-2, which are lower than Celecoxib (-8.1 kcal/mol). MD simulations (100 ns) and post simulation analysis exhibited the substantial stability and binding affinity of docked CDQ and IDG compounds with COX-2. In vitro assays indicated significant COX-2 inhibition by CDQ (IC50 = 76.91 ± 2.33 µM) and IDG (IC50 = 126.06 ± 9.44 µM). This result supported the inhibitory potential of isolated bioactive compounds against COX-2. Also, a cellular level study revealed a downregulation of COX-2 expression in tumor necrosis factor-alpha stimulated RAW 264.7 macrophages treated with CDQ and IDG. CONCLUSION: Computational and experimental analysis of CDQ and IDG from S. herbacea established their potential in the inhibition and mediation of COX-2. Hence, CDQ and IDG can be considered for therapeutic development against COX-2 linked disorders, such as inflammation and cancer. Furthermore, CDQ and IDG structures can be served as a lead compound for the development of advanced novel anti-inflammatory drugs.
