Modeling caspase-1 inhibition: Implications for catalytic mechanism and drug design.

Abstract The metabolic product of caspase-1, IL-1β, is an important mediator in inflammation and pyroptosis cell death process. Alzheimer's disease, septic shock and rheumatoid arthritis are IL-1β mediated diseases, making the caspase-1 an interesting target of pharmacological value. Many inhibitors have been developed until now, most of them are peptidomimetic with improved potency. In the present study, all-atom molecular dynamics simulations and the MM/GBSA method were employed to reproduce and interpret the results obtained by in vitro experiments for a series of inhibitors. The analysis shows that the tautomeric state of the catalytic His237 impact significantly the performance of the prediction protocol, providing evidence for a His237 tautomeric state different to the proposed in the putative mechanism. Additionally, analysis of inhibitor-enzyme interactions indicates that the differences in the inhibitory potency of the tested ligands can be explained mainly by the interaction of the inhibitors with the S2–S4 protein region. These results provide guidelines for subsequent studies of caspase-1 catalytic reaction mechanism and for the design of novel inhibitors. Graphical abstract Image 1 Highlights • Binding energies of caspase-1 inhibitors depend on the protonation state of His237. • His237 is more likely found in its neutral form with the proton on the ε-nitrogen. • Our results suggest a revision of the putative caspase-1 reaction mechanism. • Interactions with His248, Glu 250, His342, Met345 residues are essential for inhibition. [ABSTRACT FROM AUTHOR]