Structure-based discovery and molecular dynamics evaluation of dihydrorobinetin as a potential anti-osteoclastogenic RANKL inhibitor in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that destroys joints, and in vitro and in vivo studies have confirmed the significant role of osteoclasts in bone degradation associated with this disease. The receptor activator of nuclear factor-kappa B ligand (RANKL) is associated with osteoclast differentiation and bone degradation in RA. The present study investigated the inhibitory effects of phytocompounds against RANKL. Virtual screening of 10,100 phytochemicals retrieved from the IMPPAT database was performed using AutoDock Vina to identify the top 10 compounds with the best binding scores. The top ten compounds were filtered using the ADME property to identify the most promising lead compound. The lead compound was furthermore analyzed using a 1-µs molecular dynamics simulation with GROMACS to understand the stability of the complex in the system. MM-PBSA was employed for binding energy calculations, and additional post-simulation analyses, including principal component analysis, free energy landscape plotting, and VMD visualization, were performed. Dihydrorobinetin was the most promising inhibitor of the RANKL protein after filtration via ADMET analysis, with a strong binding affinity of - 8.8 kcal/mol, forming four hydrogen bonds. The 1-µs simulation revealed stable binding of dihydrorobinetin with RANKL, and the binding energy calculations performed via the MM-PBSA method showed favorable binding and stability of the complex. This study provides interesting insights into the therapeutic potential of dihydrorobinetin by inducing conformational changes in RANKL to treat bone destruction in RA, laying the groundwork for further experimental validation to confirm its efficacy and clinical potential.