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Updated: Mar 31, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Exploring dual inhibitors for STAT1 and STAT5 receptors utilizing virtual screening and dynamics simulation
Utkarsh Raj1, Himansu Kumar1, Saurabh Gupta1
1a Department of Bioinformatics , Indian Institute of Information Technology-Allahabad , CC2-4203, Jhalwa Campus, Deoghat, Allahabad , Uttar Pradesh 211012 , India.
Abstract:
Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors that transduce signals from cytokines and growth factors to the nucleus and thereby regulate the expression of a variety of target genes. Although mutations of STATs have not been reported in human tumors but the activity of several members of the family, such as STAT1 and STAT5, is deregulated in a variety of human carcinoma. STAT1 and STAT5 share a structural similarity with a highly conserved SH2 domain which is responsible for the activation of STAT proteins on interaction with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The purpose of this study is to identify domain-specific dual inhibitors for both STAT1 and STAT5 proteins from a database of natural products and natural product-like compounds comprising of over 90,000 compounds. Virtual screening-based molecular docking was performed in order to find novel natural dual inhibitors. Further, the study was supported by the 50-ns molecular dynamics simulation for receptor-ligand complexes (STAT1-STOCK-1N-69677 and STAT5-STOCK-1N-69677). Analysis of molecular interactions in the SH2 domains of both STAT1 and STAT5 proteins with the ligand revealed few conserved amino acid residues which are responsible to stabilize the ligands within the binding pocket through bonded and non-bonded interactions. This study suggested that compound STOCK-1N-69677 might putatively act as a dual inhibitor of STAT1 and STAT5 receptors, through its binding to the SH2 domain.
Insights
This study identified a novel natural compound, STOCK-1N-69677, as a potential dual inhibitor for Signal transducer and activator of transcription (STAT) proteins STAT1 and STAT5. The compound targets the SH2 domain, crucial for STAT protein activation.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Signal transducer and activator of transcription (STAT) proteins regulate gene expression by transducing signals from cytokines and growth factors.
- While STAT mutations are not found in human tumors, STAT1 and STAT5 activity is deregulated in various carcinomas.
- STAT1 and STAT5 possess a conserved SH2 domain essential for their activation and dimerization.
Purpose of the Study:
- To identify dual inhibitors targeting both STAT1 and STAT5 proteins.
- To screen a large database of natural products and natural product-like compounds for potential dual inhibitors.
- To investigate novel natural compounds for their inhibitory potential against STAT1 and STAT5.
Main Methods:
- Virtual screening using molecular docking to identify potential dual inhibitors.
- Molecular dynamics simulations of receptor-ligand complexes (STAT1-STOCK-1N-69677 and STAT5-STOCK-1N-69677) for 50 ns.
- Analysis of molecular interactions within the SH2 domains of STAT1 and STAT5.
Main Results:
- Compound STOCK-1N-69677 was identified as a potential dual inhibitor for STAT1 and STAT5.
- Molecular docking and dynamics simulations revealed conserved amino acid residues in the SH2 domain responsible for ligand stabilization.
- Detailed analysis of bonded and non-bonded interactions confirmed the binding of STOCK-1N-69677 to the SH2 domain.
Conclusions:
- Compound STOCK-1N-69677 shows promise as a dual inhibitor of STAT1 and STAT5.
- The SH2 domain is a key target for developing dual inhibitors of STAT1 and STAT5.
- This study provides a foundation for further development of natural product-based therapies targeting deregulated STAT signaling in cancer.
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