Abstract
NOD-like receptor protein 3 (NLRP3) inflammasome is a key mediator of inflammation and a promising therapeutic target. However, the discovery of novel and effective inhibitors of NLRP3 remains limited. A combined docking-based virtual screening (DBVS) and shape-based screening approach was applied to eight traditional Chinese medicine (TCM) databases to identify potential NLRP3 inhibitors. Structural similarity analysis, ADMET prediction, and molecular dynamics (MD) simulations were performed to evaluate structural novelty, pharmacokinetic properties, and binding stability. A total of 25 potential NLRP3 inhibitors were identified, each exhibiting docking scores higher than those of the reference inhibitor XE3. Structural similarity analysis revealed that the screened compounds exhibited low similarity to previously reported NLRP3 inhibitors, demonstrating their structural novelty. ADMET evaluation indicated that compounds C2, C3, and C4 exhibited favorable physicochemical and pharmacokinetic properties. Molecular dynamics (MD) simulations demonstrated that the complexes of compounds C2, C3, and C4 with NLRP3 remained stable throughout the simulations, exhibiting limited backbone fluctuations and compact conformations, as indicated by Rg values of approximately 6 Å. Solvent-accessible surface area (SASA) and polar surface area (PSA) analyses suggested that compounds C3 and C4 were tightly solvated and maintained favorable membrane permeability. Notably, binding free energy calculations revealed that all three compounds exhibited stronger binding than XE3, with compound C3 showing the most favorable energy (-48.81 ± 3.89 kcal/mol), indicating a highly stable and energetically preferred interaction with NLRP3. This study identified promising TCM-derived compounds as potential NLRP3 inhibitors, offering new directions for anti-inflammatory drug development.