Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach
Giulio Poli1, Arianna Gelain2, Federica Porta2
1a Department of Pharmacy , University of Pisa , Pisa , Italy .
Abstract:
Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein-protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors.
Insights
Researchers identified a novel compound that inhibits Signal Transducer and Activator of Transcription 3 (STAT3) dimerization. This discovery offers a promising lead for developing new STAT3 inhibitors for cancer and other diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Signal transducer and activator of transcription 3 (STAT3) is crucial for cell growth and survival.
- Aberrant STAT3 activation is implicated in various cancers and inflammatory diseases, driving the need for inhibitors.
Purpose of the Study:
- To identify novel small molecules that inhibit STAT3 dimerization.
- To validate a virtual screening workflow for discovering STAT3 inhibitors.
Main Methods:
- Screened over 1.3 million compounds using a pharmacophore model of STAT3 dimerization.
- Employed docking and molecular dynamics simulations for refinement.
- Performed STAT3 binding assays to evaluate inhibitory activity and selectivity.
Main Results:
- Identified one compound with significant STAT3 inhibitory activity and selectivity over Grb2.
- Validated the virtual screening workflow's reliability.
- The identified compound serves as a lead for developing potent STAT3 dimerization inhibitors.
Conclusions:
- The virtual screening approach successfully identified a novel STAT3 dimerization inhibitor.
- This lead compound holds potential for developing new therapeutic agents against STAT3-driven diseases.
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