Background: Emodin exhibits various pharmacological activities, including hepatoprotective effects. However, its clinical application is limited by poor absorption and low oral bioavailability. This study aimed to optimize emodin through benzoylation and to assess the hepatoprotective potential of the resulting derivatives integrating bioinformatics and in vitro methods. Methods: We conducted network pharmacology, molecular docking and molecular dynamics (MD) simulations to predict potential targets and interactions of benzoylated emodin derivatives. The derivatives were synthesized and evaluated for cytotoxicity using the MTT assay. The hepatoprotective effects were assessed in vitro using a paracetamol-induced HepG2 cell injury model. Results: Network pharmacology analysis and gene expression profiling identified four major targets—HSP90AA1, MAPK14, RELA, and PRKACA—as key liver disease-related targets of emodin and its derivatives. Molecular docking study revealed that the benzoylated emodin derivatives exhibited generally lower (more negative) binding energies compared to emodin across all four targets. MD simulations confirmed that the complex RELA with these derivatives is more stable than with emodin. These findings were consistent with in vitro assays, emodin and its derivatives increased cell viability or protected the cells up to 60–70%. Conclusion: This study provides a comprehensive evaluation of benzoylated emodin derivatives as potential hepatoprotective agents. The findings suggest that these derivatives exhibit binding affinity toward important targets related to cirrhosis, reduced toxicity to cells, and enhanced the efficacy in protecting the liver in vitro liver injury model.
Firdayani et al. (Tue,) studied this question.