Identification of selective inhibitors for Janus kinase 1: an integrated drug repurposing strategy for breast cancer

Breast cancer is the most common type of cancer and is responsible for most cancer-related deaths. Existing breast cancer treatments have inherent drawbacks, reinforcing the need to develop new ones. JAK1 is required to activate the inflammatory cytokine IL-6 class by ERBB2 receptor tyrosine kinase signalling in breast cancer cells. Conjointly, JAK1 plays a significant role in the evolution of metastatic cancer and the incessant activation of STAT3 oncogene. This emphasizes that JAK1 can be used to target breast cancer. In this study, we performed virtual screening against the FDA subset of Zinc15 database to identify potent and selective drug compounds against JAK1 protein using computational approaches. Molecular docking by AutoDock tools 1.5.7 was used to segregate the compounds based on binding affinity. Cross-docking is then used to substantiate the selectivity, followed by DFT analysis to determine the inhibitory efficiency of compounds using the B3LYP technique with the 6-31G (d,p) basis set in Gaussian 16. To validate molecular interactions between selected inhibitor compounds and JAK1 structure molecular dynamic simulations employing Gromacs 2016.3 have been done using Gromos96 2005 force field. In addition, binding free energy calculations for the JAK1-drug complexes were carried out using MM/PBSA approach. Prior to this, toxicity profile of the drugs was analysed. Results from this study have predicted exatecan, fosnetupitant and ubrogepant as viable drugs. Therefore, JAK1 inhibition has been suggested as a possible way to target breast cancer. Additional validation employing in vitro studies may aid in identifying the bioactivity of selected compounds, enabling their application in mitigating this disease condition.