Rational approach to identify newer caspase-1 inhibitors using pharmacophore based virtual screening, docking and molecular dynamic simulation studies

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Caspase-1 is a crucial enzyme in processing pro-inflammatory cytokines like IL-1β.
• Elevated IL-1β levels are linked to various inflammatory and autoimmune diseases.
• Targeting caspase-1 presents a significant therapeutic strategy for anti-inflammatory drug development.

Purpose of the Study:

• To identify novel small molecules that inhibit caspase-1 activity.
• To explore potential therapeutic agents for inflammatory conditions.
• To develop new anti-inflammatory drugs.

Main Methods:

• Integrated virtual screening combining pharmacophore mapping and molecular docking.
• Generation of a ligand-based 3D pharmacophore model.
• Screening of chemical databases (ZINC and Maybridge) followed by ADMET filtering and docking analysis.
• Cross-docking studies against related caspases (1, 3, 7, 8) for specificity.
• Molecular dynamics simulations of top-scoring compounds.

Main Results:

• A validated pharmacophore hypothesis (Hypo 1) was developed.
• Several virtual hits were identified and filtered.
• Cross-docking revealed specific interactions for caspase-1 inhibition.
• Top-ranked molecules (ZINC00885612, ZINC72003647, BTB04175, BTB04410) were identified.
• Molecular dynamics simulations provided insights into protein-ligand interactions.

Conclusions:

• The study successfully identified promising small molecules as potential caspase-1 inhibitors.
• These identified compounds can serve as lead structures for novel anti-inflammatory agents.
• The findings support the development of new therapeutics for IL-1β-mediated inflammatory diseases.