Elucidating the hepatoprotective mechanisms of Vernonia cinerea phytoactives in drug-induced liver injury by computational approach of network pharmacology, molecular docking and dynamic simulation studies

Abstract

Abstract Drug-Induced Liver Injury (DILI), also known as Hepatotoxicity, refers to unexpected liver damage triggered by common medications, which harms hepatocytes and other liver cells. This damage can either be intrinsic, appearing shortly after drug exposure, or idiosyncratic, emerging from intricate interactions of individual and environmental factors with the drug. Despite precautions taken during drug development, preventing DILI remains a daunting task due to insufficient preventive guidelines. Herbal remedies such as Vernonia cinerea, known as purple fleabane or Sahadevi, might provide a potential treatment for DILI. Traditionally, this plant has been used for ailments like hepatitis, fever, diabetes, and asthma, demonstrating a wide array of pharmacological properties. Nonetheless, traditional medicine frequently lacks adequate scientific data on these herbal remedies' composition, action mechanisms, and ADMET profiles.The present study's goal is to uncover potential phytoconstituents in V. cinerea associated with DILI or hepatotoxicity and shed light on their possible treatment mechanisms using chemo-informatic tools and databases like STRING, Cytoscape 3.6.1 for network pharmacology, PyRx 0.8, DSV 2022 for molecular docking, and GROMACS for dynamic simulation studies.Out of the twenty-six phytoactives, Feroxin A and Apocyanin B demonstrated the highest drug-likeness scores, i.e., 1.1 and 0.94, respectively. Further docking studies showed that Apocyanin B, when complexed with Epidermal growth factor receptor (EGFR), displayed the lowest binding energy (-9.6kcal/mol) and formed complex stability with 11 residues: Leu718, Val726, Ala743, Lys745, Met766, Gln791, Leu792, Met793, Arg841, Leu844, and Lys852 over a 100 ns molecular dynamic production run.In contrast, the Erlotinib-EGFR complex was used as a reference to validate the Apocyanin B protein with the EGFR complex. Erlotinib docking exhibited a binding energy of -6.7kJ/mol and created complex stability through 11 residues like Leu718, Val726, Ala743, Lys745, Thr790, Leu792, Gly796, and Leu844 during the dynamic state at a 100ns run.The hepatoprotective capability of Vernonia cinerea may be attributed to the presence of phytoactives, particularly Apocyanin B, which modulate targets such as AKT1, PIK3CA, MAPK, HRAS, and EGFR. The findings from this study illuminate the molecular mechanisms that contribute to the hepatoprotective advantages of Vernonia cinerea.