Computational investigation of selected crocus sativus bioactive compounds as potential JAK2 kinase inhibitors

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that serves as a key regulator of the JAK-STAT signalling pathway, that influences multiple cellular functions, including cell growth, differentiation, survival and the modulation of immune responses. Constitutive activation of JAK2 is closely associated with hematological malignancies and several solid tumours, making it an important therapeutic target for anticancer drug discovery. Although clinically approved JAK2 inhibitors have shown therapeutic benefits, their long-term use is restricted by toxicity, adverse effects and the chances of drug resistance, prompting the search for safer natural alternatives. Bioactive constituents of Crocus sativus possess diverse pharmacological activities, including anticancer properties, however, their molecular interactions with the catalytic domain of JAK2 remain poorly characterized. In this work, an integrated computational approach is employed to study the interaction of selected phytochemicals of C. sativus with the ATP-binding kinase domain of human JAK2. Molecular docking predicted favourable binding orientations within the ATP-binding pocket for all compounds through interactions with conserved residues. However, MD simulations revealed distinct differences in binding stability. Crocin, crocetin and safranal maintained stable interactions with the ATP-binding region throughout the simulation, whereas picrocrocin gradually migrated away from the binding pocket. These findings identify crocin, crocetin and safranal as promising natural JAK2-binding candidates, whereas picrocrocin appears to be a false-positive docking hit due to its lack of sustained binding during MD simulation.