Application of bioactive molecular networking to identify corneal-cytoprotective compounds from Dialium cochinchinense Pierre. leaves

Dry eye disease (DED) requires innovative therapeutic strategies targeting inflammation and oxidative stress. In this study, we demonstrate for the first time that Dialium cochinchinense leaf extracts exhibited significant anti-inflammatory activities by inhibiting the nuclear transcription factor-κB (NF-κB) signaling pathway in macrophages. Additionally, these extracts showed notable antioxidant and cytoprotective capabilities, effectively mitigating oxidative stress-induced damage in corneal epithelial cells. We employed an advanced bioactive molecular networking strategy to prioritize and isolate key bioactive compounds, providing distinct advantages over traditional phytochemical screening methods. This approach led to the discovery of a new compound, 6S,9R-2′-O-sinapoyl-roseoside, and 11 known phenolic compounds. Notably, 10 of these compounds exhibited substantial corneal-cytoprotective effects in vitro. Network pharmacology analysis revealed 65 key shared targets between these compounds and DED, linked to PI3K/AKT and MAPK pathways critical for inflammation and cell survival. Subsequent molecular docking and molecular dynamics simulations confirmed stable and high-affinity binding interactions between the identified lead compounds and key protein targets implicated in DED. These findings demonstrate D. cochinchinense leaf extract and its bioactive constituents are promising natural candidates for DED, providing a scientific basis for further translational research and potential drug development.