A panorama to mine “bioactive X” against progressive deterioration of liver disease: from NAFLD to HCC

Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The targets of the four hepatic-diseases were browsed by DisGeNET and OMIM, then, the intersecting targets were identified by Venn diagram. Protein-protein interaction (PPI) networks were constructed on STRING database with the aid of R program. The uppermost target(s) against NAFLD, NASH, LC, and HCC were filtered by degree centrality (DC), and betweenness centrality (BC) value. We utilized the Selleckchem (compound repository website) to retrieve the ligand(s) for the target(s), hereby, confirmed the affinity via molecular docking test (MDT), density functional theory (DFT), and toxicity prediction. The final targets (295) were identified by DisGeNET and OMIM, the core PPI networks comprised 26 nodes, and 248 edges with two key targets (INS, and IL6) in the highest 30% betweenness centrality (BC). The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (-12.1 kcal/mol), and IL6- Forsythoside B (-11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.