Abstract
Liver diseases account for over two million deaths annually, amounting to 4% of mortality worldwide, underscoring the need for development of novel preventive and therapeutic strategies. The growing interest in natural hepatoprotective agents highlights the potential of traditional medicine for modern drug discovery, though unlocking their molecular complexity requires advanced tools. This study integrates cutting-edge computational techniques with traditional herbal knowledge to identify potential hepatoprotective compounds. Protein targets implicated in liver disorders were identified through network pharmacology and by leveraging the rich molecular diversity inherent in herbal compounds, phytocompounds were selected. The Gene Ontology, Kyoto Encyclopedia of Genes and Genome data were compiled and enrichment analysis was performed using the DAVID database. Molecular docking of selected phytocompounds with top five protein targets helped identify 14 compounds which were employed for building the pharmacophore model. In virtual screening, among 1089 compounds screened, 10 compounds were identified as potential hits based on their predicted scores and alignment with pharmacophore features. The interactions of resulting hits were then analyzed through redocking studies and validated through molecular dynamics simulation and ADMET studies. Notably, (2S,5E)-2-(3,4-Dihydroxybenzyl)-6-(3,4-dihydroxyphenyl)-4-oxo-5-hexenoic acid and 5'-hydroxymorin emerged as lead compounds for further investigation. Both compounds exhibited significant binding affinities with specific amino acids in selected targets, suggesting their potential to modulate key pathways involved in hepatic disorders. Our findings demonstrate the utility of this integrated approach which transits beyond traditional trial-and-error methods. This approach will accelerate the discovery of novel hepatoprotective compounds, providing deeper insights into their mechanistic pathways and action.