Inhibition of IRF3-STING axis interaction in silicosis using natural compounds: an in-silico study using molecular docking, ADMET, molecular dynamics and MMPBSA approach

Silicosis is a chronic occupational lung disease characterized by persistent inflammation driven by the activation of the cGAS-STING pathway, leading to the downstream activation of IRF3. To develop a natural compound library of COCONUT database for this investigation, Lipinski’s rule of five was used and we explored the potential of these compounds to disrupt the IRF3-STING interaction, thereby mitigating the inflammatory response. Molecular docking and molecular dynamics (MD) simulations were employed to assess the binding stability and interaction dynamics of these compounds with IRF3. The stable RMSD values indicate that the protein-ligand complexes maintained structural integrity throughout the simulation period. The compounds also demonstrated drug-like characteristics, a promising safety profile, and formed stable complexes with the target protein. Further, decomposition of binding free energy highlighted the key contributions of IRF3 residues VAL295, ASP308, PRO324, and ARG338 interacting with the selected compounds, potentially inhibiting the IRF3-STING interaction. The origin of the selected compounds was determined using ClassyFire, classifying compound CNP0310627 as a burfenolide and compound CNP0200121 as a psoralen. Both classes are recognized for their anti-inflammatory properties, reinforcing the therapeutic potential of these compounds in reducing inflammation associated with silicosis. Our findings suggest that these compounds could serve as promising candidates for further investigation in the development of anti-inflammatory therapeutic molecules in the cGAS-STING-IRF3 signaling pathway. However, to fully assess the therapeutic potential of these compounds, further in vitro and in vivo studies are required to validate their efficacy and safety in modulating the STING-IRF3 pathway.