Unveiling a novel ellagic acid derivative as a potent lipoxygenase (LOX) inhibitor: integration of computational modeling and experimental validation.

Abstract

Cornus macrophylla has been traditionally recognized for its medicinal properties, particularly in managing inflammatory conditions. However, a scientific understanding of its bioactive constituents and mechanisms remains underexplored. This study aimed to isolate and characterize bioactive compounds from the bark of C. macrophylla and evaluate their anti-inflammatory potential through in silico and in vitro analyses. A total of ten compounds, including an ellagic acid derivative and nine steroids and triterpenes, were isolated. Comprehensive analyses integrating molecular docking, ADMET profiling, and density functional theory (DFT) calculations were conducted to elucidate the molecular and anti-inflammatory properties. Experimental validation was performed to confirm the findings. 1,2,3-trimethoxychromeno[5,4,3-cde][1,3]dioxolo[4,5-h]chromene-5,11-dione (1) emerged as the most active compound among those tested, demonstrating moderate inhibition of lipoxygenase (LOX), exhibiting an IC50 value of 78.1 ± 0.03 µM. It also exhibited measurable suppression of respiratory burst activity in human neutrophils, achieving an IC50 of 298.21 ± 0.037 µM, comparable to the benchmark anti-inflammatory agent, Indomethacin (IC50: 271.14 ± 0.032 µM). Molecular docking studies revealed that compound 1, strongly interacts with 15-LOX, demonstrating a binding affinity of -7.038 kcal/mol and forming stable interactions with key active site residues. ADMET profiling and DFT analysis indicated its favourable drug-like properties, reinforcing its potential as a therapeutic candidate. The findings highlight compound (1) as a potent natural inhibitor of LOX, with significant anti-inflammatory activity validated through both experimental and computational approaches. Its efficacy and drug-likeness underscore its therapeutic potential for developing novel anti-inflammatory agents. Further studies are warranted to explore its clinical applicability.