Computational dissection through network pharmacology and structure-based analysis unravels mechanistic actions of bioactive compounds in a hepatoprotective herb, <i>Picrorhiza kurroa</i> for the treatment of NAFLD and NASH

Non-Alcoholic fatty liver disease has become a silent pandemic worldwide with no authorized medicine available. <i>Picrorhiza kurroa</i> is a traditional hepatoprotective herb wherein extracts provide therapeutic efficacy but not the individual compounds. Hence, the aim of the study is exploration of active molecules in <i>P. kurroa</i> extracts and identification of mechanistic actions to pinpoint potential leads towards drug development. We employed network pharmacology to identify the significance of combinatorial effect of compounds on multiple targets. The NAFLD/NASH associated genes encoding protein targets overlapped with the predicted protein targets of <i>P. kurroa</i> compounds. Then, overlapping targets were considered further to capture the interactive targets from Protein-Protein-Interaction network of NAFLD and NASH. The networks were generated to capture the role of proteins in different signaling pathways, diseases, and effective compounds as therapeutics. Furthermore, structural, and biophysical analysis was performed for significant complexes. We observed that the compounds like astragalin, Picroside-I, Vernicoside, Rutin, Quercetin, Kaempferol, Gallic acid, Ellagic acid in <i>P. kurroa</i> acted synergistically by enhancing the bioavailability of active compounds and affecting various morbidities of NAFLD through involvement in different signaling and disease pathways such as oxidative phosphorylation, FoxO signaling, inflammation, several cancerous and diabetic pathways. The network pharmacology revealed the interactive behavior of proteins involved in NAFLD treated by <i>P. kurroa</i> compounds. Furthermore, molecular docking and molecular dynamic simulation study showed potential candidates in therapeutics. Overall, the study suggested multi-target drug discovery for treating complex diseases by providing leads in herbal extracts as potential therapeutic botanicals.