Computational modeling and in vitro evaluation identified natural product-Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat β-thalassemia.

Aberrant activity of Janus kinase 2 (JAK2) is a known driver of several myeloproliferative disorders, including polycythemia vera, and thalassemia. Several inhibitors have been proposed to inhibit JAK2 activity in order to control the disease progression. Ruxolitinib and fedratinib that targets JAK2 kinase have been approved for use in myeloproliferative neoplasms patients. Experimental structures of JAK2 complexed with ruxolitinib provide insights into critical interactions of ruxolitinib. In this work, using a high-throughput virtual screening followed by experimental validations, we have identified a novel natural product from ZINC database that interacts with JAK2 in a manner similar to ruxolitinib and inhibits the activity of JAK2 kinase. Molecular dynamics simulations and MMPBSA method show binding dynamics and stability of our identified lead compound. Kinase inhibition assays show that our identified lead molecule inhibits JAK2 kinase at a nanomolar range, indicating a plausibility that the identified lead molecule can be further studied as natural product inhibitor of JAK2 kinase.