Identification of novel STAT3 inhibitors for liver fibrosis, using pharmacophore-based virtual screening, molecular
Huma Rafiq1, Junjian Hu2, Mohammed Ageeli Hakami3
1Department of Biochemistry, Computational Medicinal Chemistry Laboratory, Abdul Wali Khan University, Mardan, Pakistan.
Abstract:
The signal transducer and activator of transcription 3 (STAT3) plays a fundamental role in the growth and regulation of cellular life. Activation and over-expression of STAT3 have been implicated in many cancers including solid blood tumors and other diseases such as liver fibrosis and rheumatoid arthritis. Therefore, STAT3 inhibitors are be coming a growing and interesting area of pharmacological research. Consequently, the aim of this study is to design novel inhibitors of STAT3-SH3 computationally for the reduction of liver fibrosis. Herein, we performed Pharmacophore-based virtual screening of databases including more than 19,481 commercially available compounds and in-house compounds. The hits obtained from virtual screening were further docked with the STAT3 receptor. The hits were further ranked on the basis of docking score and binding interaction with the active site of STAT3. ADMET properties of the screened compounds were calculated and filtered based on drug-likeness criteria. Finally, the top five drug-like hit compounds were selected and subjected to molecular dynamic simulation. The stability of each drug-like hit in complex with STAT3 was determined by computing their RMSD, RMSF, Rg, and DCCM analyses. Among all the compounds Sa32 revealed a good docking score, interactions, and stability during the entire simulation procedure. As compared to the Reference compound, the drug-like hit compound Sa32 showed good docking scores, interaction, stability, and binding energy. Therefore, we identified Sa32 as the best small molecule potent inhibitor for STAT3 that will be helpful in the future for the treatment of liver fibrosis.
Insights
Researchers computationally designed novel STAT3 inhibitors to treat liver fibrosis. The study identified Sa32 as a potent small molecule inhibitor, showing good stability and binding interactions with STAT3, offering future therapeutic potential.
Area of Science:
- Pharmacology and Computational Chemistry
Background:
- Signal transducer and activator of transcription 3 (STAT3) is crucial for cellular processes.
- STAT3 over-expression is linked to various cancers and diseases like liver fibrosis and rheumatoid arthritis.
- Developing STAT3 inhibitors is a significant area of pharmacological research.
Purpose of the Study:
- To computationally design novel STAT3 inhibitors.
- To identify potential treatments for liver fibrosis by targeting STAT3.
Main Methods:
- Pharmacophore-based virtual screening of over 19,481 compounds.
- Molecular docking and analysis of binding interactions with the STAT3 receptor.
- ADMET property calculation, drug-likeness filtering, and molecular dynamic simulations.
Main Results:
- Virtual screening identified potential STAT3 inhibitors.
- Molecular docking and simulations evaluated compound efficacy and stability.
- Sa32 demonstrated favorable docking scores, interactions, stability, and binding energy compared to a reference compound.
Conclusions:
- Sa32 was identified as a potent small molecule inhibitor of STAT3.
- Sa32 shows promise for the future treatment of liver fibrosis.
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