Identification of Active Phytochemicals to Inhibit Signal Transducer and Activator of Transcription 5A (STAT5A) Dimerization for Prostate Cancer Therapy: An In Silico Approach.

Background: The Src Homology 2 (SH2) domain, the most conserved region of STAT5a/b (aa 573- 712), is crucial for receptor-specific recruitment and STAT5 dimerization, making it a therapeutic target in prostate cancer (PCa).

Objectives: This study explored the SH2 domain of STAT5a and carried out the identification of natural STAT5a inhibitors.

Methods: Using template-based homology modeling, we constructed the structure of human STAT5a (VP1P) and compared it with its 3D crystal of the STAT5a protein obtained from the RCSB database and the model generated by the AlphaFold database. In this study, we carried out molecular docking studies using AutoDock Vina on the top 500 natural compounds identified through a pharmacophore search of the ZINC database using ZINCPharmer. Furthermore, the top ten compounds with the highest binding energies were evaluated for their drug-likeness and ADMET properties using SWISS ADME and ProTox-II, followed by 100 ns molecular dynamics (MD) simulations using the Desmond module of the Schrodinger suite.

Results: Docking studies revealed Pedunculagin (-10.5 kcal/mol), Folic acid (-10.1 kcal/mol), Chebulinic acid (- 10.0 kcal/mol), Chebulagic acid (-9.8 kcal/mol), and Oleandrin (-9.8 kcal/mol) as the top candidates, compared to the STAT5 inhibitor (Phase-II Clinical Trial) (-8.5 kcal/mol). ADMET analysis confirmed their safety profiles. MD simulations showed stable protein-ligand complexes, with all compounds interacting with the conserved Arg638 residue at the active site, similar to the STAT5 inhibitor.

Conclusion: Pedunculagin demonstrated the strongest binding energy and stability, making it a promising candidate for further development as a novel lead compound to disrupt STAT5a/b dimerization in PCa therapy.