Structure-Based Drug Repurposing Reveals State-Independent Binding of MCC950 to the NLRP3 Inflammasome: Implications for Alzheimer’s Disease

Background Alzheimer disease (AD) is extensively accepted as a chronic neuroinflammatory disease, and the NLRP3 inflammasome is one of the critical factor in the pathogenesis of the disease. Neuroprotective activity in preclinical models of AD has been shown with MCC950, a potent small molecule NLRP3 inhibitor. Nevertheless, the molecular mechanism of NLRP3 repression is not fully elucidated, especially since the protein displays a significant conformational flexibility in the activation process. The typical structure based drugs discovery paradigm that employs the single protein conformation might not reproduce the dynamic properties of the protein ligand interaction. Methods We employed a multi-structure molecular docking technique to evaluate binding characteristics of three known NLRP3 inhibitors MCC950, oridonin, and parthenolide across four experimentally resolved human NLRP3 structures (PDB: 6NPY, 7PZC, 8SXN, 9GU4) representing inactive, intermediate, and active conformational states. Binding affinity, interaction networks (hydrogen bonds, hydrophobic contacts, π-π stacking), pose stability (RMSD analysis), and binding depth were sequentially compared across conformations using AutoDock Vina, PLIP, and PyMOL. Results MCC950 exhibited strong state independent binding with a uniformly high affinity (mean docking score: -9.3 ± 0.2 kcal/mol), conserved hydrogen bonding binding with ARG167 and TYR381, and comprehensive hydrophobicity as well as remarkably low pose variability in all the conformations. On the contadictory, the interaction between oridonin and parthenolide was conformation reliant with reduced strength, with inconsistent patterns of interaction and possessing greater pose instability (mean RMSD: 3.1 and 4.1 A, respectively). MC950 was very ingrained in the NACHT domain pocket (76–80% buried), but natural compounds were attached more marginally. Conclusions MCC950 displays a better conformational stability than natural NLRP3 inhibitors and it can bind to a diversity of protein states in a stable manner. This binding property is independent of the state and act as a molecular explanation of MCC950 and its stable efficacy in preclinical investigations and its therapeutic potential in AD and other neuroinflammatory disorders. The multi structure docking method offers a more realistic structure grounded approach to drug discovery of conformationally dynamic proteins.