Exploring mimosamycin as a Janus kinase 2 inhibitor: A combined computational and experimental investigation.

Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play a crucial role in signal transduction pathways. JAK2 has been implicated in the pathogenesis of leukemia, making it a promising target for research aimed at reducing the risk of this disease. This study examined the potential of mimosamycin as a JAK2 inhibitor using both in vitro and in silico approaches. We performed a kinase assay to measure the IC of mimosamycin for JAK2 inhibition, which was found to be 22.52 ± 0.87 nM. Additionally, we utilized molecular docking, molecular dynamics simulations, and free energy calculations to investigate the inhibitory mechanism at the atomic level. Our findings revealed that mimosamycin interacts with JAK2 at several key regions: the hinge-conserved region (M929, Y931, L932, and G935), the G loop (L855 and V863), and the catalytic loop (L983). To enhance the binding affinity of mimosamycin toward JAK2, we designed derivatives with propanenitrile and cyclopentane substitutions on the naphthoquinone core structure. Notably, these newly designed analogs exhibited promising binding patterns against JAK2. These insights could aid in the rational development of novel JAK2 inhibitors, with potential applications in the treatment of leukemia and related diseases.