Computational evaluation of NOD-like receptor pyrin domain-containing 3 inflammasome inhibitors for endodontic inflammation: A molecular docking analysis of synthetic and phytochemical compounds.

Context: The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome drives interleukin-1 β-mediated inflammation in endodontic pathologies, including pulpitis and apical periodontitis. Despite advances in chemomechanical preparation techniques, residual inflammation and persistent bacterial infection remain significant challenges. Targeting the NLRP3 inflammasome pathway represents a promising therapeutic strategy. This study evaluated binding interactions of synthetic inhibitors and phytochemicals with NLRP3 inflammasome components using molecular docking and binding free energy calculations. Aims: The study aimed to computationally evaluate synthetic and phytochemical inhibitors targeting the NLRP3 inflammasome in endodontic inflammation using molecular docking and molecular mechanics/generalized born surface area (MM-GBSA) analysis. Subjects and Methods: Molecular docking simulations using Schrödinger Glide Extra Precision mode assessed ligand-target interactions against three critical proteins: full-length NLRP3 (homology model), NLRP3- PyMOL Docking / Python docking-related file (ligand or docking preparation file) (PYD) domain Protein Data Bank (3D structure file for proteins/biomolecules) (PDB: 3QF2), and caspase-1 (PDB: 1RWK). Binding free energies were estimated using MM-GBSA calculations with the OPLS3 force field. The compound library consisted of five phytochemicals and five synthetic inhibitors, all filtered for drug-likeness using Lipinski's rule of five. Results: CY-09 exhibited superior NLRP3 binding affinity (Glide Score: -6.476 kcal/mol; MM-GBSA: -58.32 kcal/mol) through hydrogen bonding with Arg351 and hydrophobic interactions. Among phytochemicals, apigenin displayed optimal binding (-5.690 kcal/mol; -51.23 kcal/mol) via hydrogen bonding and π-π stacking. Pralnacasan showed the highest caspase-1 affinity (-5.556 kcal/mol; -54.89 kcal/mol). Conclusions: This analysis identifies CY-09 and pralnacasan as lead synthetic inhibitors, while establishing apigenin and curcumin as promising phytochemical alternatives. These findings provide a structure-based framework for developing adjunctive anti-inflammatory therapies. Experimental validation through molecular dynamics simulations, cell-based assays, and animal models remains essential.