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

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Interleukin-1 beta (IL-1β), a product of caspase-1, is key in inflammation and pyroptosis.
• Diseases like Alzheimer's, septic shock, and rheumatoid arthritis are linked to IL-1β, highlighting caspase-1 as a therapeutic target.

Purpose of the Study:

• To interpret in vitro experimental results for caspase-1 inhibitors using computational methods.
• To investigate the impact of the catalytic His237 tautomeric state on prediction accuracy.
• To elucidate the key interactions driving differences in inhibitor potency.

Main Methods:

• All-atom molecular dynamics simulations.
• Molecular Mechanics with Generalized Born Surface Area (MM/GBSA) method.
• Analysis of inhibitor-enzyme interactions.

Main Results:

• The tautomeric state of catalytic His237 significantly affects prediction protocol performance, suggesting a different state than previously proposed.
• Inhibitor potency differences are primarily attributed to interactions within the S2-S4 protein region.
• Computational methods successfully reproduced and interpreted in vitro experimental findings.

Conclusions:

• The His237 tautomeric state is crucial for accurate caspase-1 inhibitor modeling.
• Targeting the S2-S4 region offers a promising strategy for designing potent caspase-1 inhibitors.
• These findings provide valuable insights for future research on caspase-1 mechanisms and drug design.