Multi-Fold Computational Analysis to Explore JAK2 and STAT5 Potential Inhibitors for Modulation of Cancer

Background: The Janus kinase 2-Signal Transducer and Activator of the Transcription 5 pathway (JAK2-STAT5 pathway) is a signaling pathway that plays a role in a variety of cellular processes, including cell growth, proliferation, and survival. Dysregulation of the JAK2-STAT5 pathway has been linked to several diseases, including cancer and its relapse. This study performed molecular docking simulation and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) investigations on selected bioactive compounds against JAK2-STAT5 proteins for cancer drug discovery. Methods: JAK2 protein (Protein Data Bank (PDB) ID: 3Q32), STAT5 protein (PDB ID: 1Y1U), and 313 bioactive compounds, including standard anticancer drugs, were used for molecular docking simulation. The proteins' crystal structures were retrieved from PDB and prepared using BIOVIA Discovery Studio. The chemical structures of the compounds were retrieved from the National Center for Biotechnology Information (NCBI) PubChem database and prepared using the Open Babel and VConf software. PyRx equipped with AutoDock vina was used to perform molecular docking. The ADMET parameters for the top-performing compounds were determined using the SwissADME and pkCMS web servers. Results: The result from this study suggests that the following top-performing compounds, hypericin, withanolide, tomatidine, silymarin, baicalin, and diosmin, had the best binding energies with the potentials to serve as scaffolds or leads for new drug discovery against cancer. The ADMET study revealed that hypericin, baicalin, and diosmin violated more than one Lipinski's rule of 5 (RO5), which implies poor oral bioavailability, while withanolide, tomatidine, silymarin, ailanthone, elliptinium, ellipticine, etc. did not violate the rule which implies that they would be the best oral drug candidates based on the RO5 rules. Conclusions: The top-performing compounds, hypericin, withanolide, tomatidine, silymarin, baicalin, and diosmin, could serve as potential inhibitors/therapeutics against cancer caused by JAK2-STAT5 dysregulation.