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Published on: December 18, 2013
In Silico Screening for Small Molecules to Alter Calpain Proteolysis through Modulating Conformation Changes Induced
Pitambar Poudel1, Ivan Shapovalov2,3, Shailesh Kumar Panday1
1Department of Physics & Astronomy, College of Science, Clemson University, Clemson, South Carolina 29634, United States.
Journal of Chemical Information and Modeling
|May 20, 2025
Summary
Researchers identified small molecules to modulate calpain activity, crucial for treating diseases. These compounds target the calpain-2 catalytic (CAPN2) and regulatory (CAPNS1) subunit interaction, revealing a novel allosteric mechanism for therapeutic development.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Dysregulated calpain activity is implicated in various diseases.
- No specific drugs currently target calpain functionality, representing a significant unmet medical need.
- Calpain activity requires heterodimerization of calpain-2 catalytic (CAPN2) and regulatory (CAPNS1) subunits.
Purpose of the Study:
- To identify small molecules that modulate calpain activity through *in silico* drug discovery.
- To target the CAPN2-CAPNS1 protein-protein interaction (PPI) interface to disrupt heterodimerization or alter CAPN2 conformation.
- To explore novel therapeutic strategies for calpain-related diseases.
Main Methods:
- Utilized *in silico* screening of ~3.6 million small molecules against the CAPN2-CAPNS1 interface.
- Selected 20 small molecules predicted to disrupt hydrogen bonds at the interface for experimental validation.
- Employed calpain activity assays and CAPN2-CAPNS1 PPI assays.
- Performed molecular simulations to elucidate the mechanism of action.
Main Results:
- Five small molecules inhibited calpain activity (ranging from 31.1% to 69.8%).
- Two small molecules enhanced calpain activity (129.2% and 163.0%).
- Observed a lack of correlation between PPI assay results and protease activity modulation, suggesting an allosteric mechanism.
Conclusions:
- Small molecules can modulate calpain activity through mechanisms beyond disrupting heterodimerization.
- An allosteric mechanism, altering conformational changes necessary for activity, was identified.
- These findings offer a new avenue for developing therapeutics targeting calpain dysregulation in diseases.
