Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases
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Published on: August 1, 2013
R N V Krishna Deepak1, Ahmad Abdullah2, Priti Talwar2
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore.
Abstract:
The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed 5 compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that 4 out of the 5 drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the 4 compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of 4 novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.
Insights
Researchers identified four FDA-approved drugs that inhibit caspase-3/7, key regulators of apoptosis. These novel non-peptide allosteric inhibitors offer potential therapeutic strategies for diseases linked to abnormal cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Apoptosis regulation is crucial, with caspases, particularly caspase-3/7, acting as key executioners.
- Dysregulation of apoptosis contributes to various human diseases.
- Existing peptide-based caspase inhibitors have limitations due to non-specific activity and poor drug properties.
Purpose of the Study:
- To identify FDA-approved drugs for repurposing as novel allosteric inhibitors of caspase-3/7.
- To explore alternative therapeutic strategies beyond traditional peptide inhibitors.
Main Methods:
- Virtual screening of FDA-approved drugs against an allosteric pocket of caspase-3/7.
- Experimental validation of top-scoring compounds using enzymatic assays.
- In vitro inhibition assays with recombinant caspase-3.
- Structural analysis of drug-target interactions via docking poses.
Main Results:
- Four out of five tested FDA-approved drugs demonstrated effective inhibition of caspase-3 enzymatic activity in vitro.
- Inhibitory concentrations (IC50) ranged from approximately 10-55 μM.
- Structural analysis indicated specific non-covalent interactions within the allosteric pocket, suggesting disruption of the active site.
Conclusions:
- Identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from existing FDA-approved drugs.
- These compounds represent promising candidates for further development in treating diseases associated with apoptosis dysregulation.
- Drug repurposing offers an efficient pathway for discovering new therapeutic agents.
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