Molecular docking and dynamics guided approach to identify potential anti-inflammatory molecules as NRF2 activator to protect against drug-induced liver injury (DILI): a computational study

Inflammation and oxidative stress can contribute to the etiology of metabolic and chronic illnesses. The ability to prevent oxidative stress induced diseases such as cancer, cardiovascular disease, Alzheimer's disease, and others has been the subject of global research. Drug-induced liver injury (DILI) pathogenesis can be either due to oxidative stress or inflammatory response elicited by the drug, its metabolite, or herbal supplements. Our present research uses computational studies to identify a molecule with anti-inflammatory properties that can operate as an NRF2 activator. Acquiring and preparing the KEAP1-NRF2 Protein (PDB: 4L7D) with Schrodinger Suite was followed by developing a ligand library (Anti-inflammatory library downloaded from ChemDiv database). Molecular docking studies were performed in HTVS, SP, and XP modes, respectively. Based on the docking score, interaction, ADMET and binding free energy, the top ten compounds were selected and subjected to induced-fit docking (IFD) analysis for further study. The top three molecules were chosen for a molecular dynamics (MD) simulation study. Using the Desmond module of the Schrodinger Suite, the stability of the protein-ligand complex and protein-ligand contact throughout 100ns were evaluated during the MD simulation study. In our study, it was observed that three compounds exhibit exceptional stability and retain the essential interaction throughout the studies, and it is anticipated that these compounds may act as effective NRF2 activators. Further in vitro and in vivo assessments can be conducted to determine its potential to prevent DILI via acting as an NRF2 activator for future drug development.