In silico drug discovery and molecular dynamics simulation for targeting neonatal pneumonia and bronchopulmonary dysplasia.

Background: Neonatal pneumonia and bronchopulmonary dysplasia (BPD) are major causes of morbidity and mortality in preterm infants, driven by excessive inflammation involving the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This study employed Methods: The NLRP3 NACHT domain (PDB ID: 7ALV) served as the target. A library of FDA-approved drugs and TCM-derived compounds underwent molecular docking with AutoDock Vina. Top hits were evaluated for ADMET properties using SwissADME, pkCSM, and admetSAR. Selected complexes (Hinokiflavone, Theaflavin, Sciadopitysin, Liquiritin apioside, Tigogenin) were subjected to 200 ns all-atom MD simulations in GROMACS and MM/PBSA binding free energy analysis. Results: Hinokiflavone and Theaflavin exhibited the strongest docking scores (-10.8 and -10.4 kcal/mol), superior MD stability (lowest RMSD: 0.21 ± 0.02 nm and 0.23 ± 0.03 nm; high hydrogen bond occupancy: 78% and 82%), and most favorable MM/PBSA binding energies (-55.8 and -55.2 kcal/mol), driven by van der Waals and electrostatic interactions. They showed acceptable ADMET profiles with high intestinal absorption and low BBB penetration. Conclusion: Hinokiflavone and Theaflavin emerge as promising NLRP3 inhibitors with stable binding to the NACHT domain and cytoprotective effects in lung epithelial cells. These TCM-derived compounds warrant further preclinical investigation as potential targeted therapies to mitigate inflammation in neonatal pneumonia and BPD.