SMU-CX1

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 mol. docking simulation and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) investigations on selected bioactive compounds against JAK2-STAT5 proteins for cancer drug discovery.JAK2 protein (Protein Data Bank (PDB) ID: 3Q32), STAT5 protein (PDB ID: 1Y1U), and 313 bioactive compounds, including standard anticancer drugs, were used for mol. docking simulation.The proteins' crystal structures were retrieved from PDB and prepared using BIOVIA Discovery Studio.The chem. structures of the compounds were retrieved from the National Center for Biotechnol. Information (NCBI) PubChem database and prepared using the Open Babel and VConf software.PyRx equipped with AutoDock vina was used to perform mol. docking.The ADMET parameters for the top-performing compounds were determined using the SwissADME and pkCMS web servers.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.The top-performing compounds, hypericin, withanolide, tomatidine, silymarin, baicalin, and diosmin, could serve as potential inhibitors/therapeutics against cancer caused by JAK2-STAT5 dysregulation.

Over 30-35% of patients down with AML are caused by mutations of FLT3-ITD and FLT3-TKD which keeps the protein activated while it activates other signaling proteins downstream that are involved in cell proliferation, differentiation, and survival. As drug targets, many inhibitors are already in clinical practice. Unfortunately, the average overall survival rate for patients on medication suffering from AML is 5 years despite the huge efforts in this field. To perform docking simulation and ADMET studies on selected phytochemicals against FLT3 protein receptor for drug discovery against FLT3 induced AML, molecular docking simulation was performed using human FLT3 protein target (PDB ID: 6JQR) and 313 phytochemicals with standard anticancer drugs (Sorafenib and Gilteritinib in addition to other anticancer drugs). The crystal structure of the protein was downloaded from the protein data bank and prepared using Biovia Discovery Studio. The chemical structures of the phytochemicals were downloaded from the NCBI PubChem database and prepared using Open Babel and VConf softwares. Molecular docking was performed using PyRx on Autodock Vina. The ADMET properties of the best performing compounds were calculated using SwissADME and pkCMS web servers. The results obtained showed that glabridin, ellipticine and derivatives (elliptinium and 9-methoxyellipticine), mezerein, ursolic acid, formononetin, cycloartocarpesin, hypericin, silymarin, and indirubin are the best performing compounds better than sorafenib and gilteritinib based on their binding affinities. The top-performing compounds which had better binding and ADMET properties than sorafenib and gilteritinib could serve as scaffolds or leads for new drug discovery against FLT3 induced AML.Communicated by Ramaswamy H. Sarma.