Consensus Virtual Screening and Ex Vivo Evaluation of Novel JAK2/STAT1,3 Inhibitors
Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is a key therapeutic target for inflammatory and neoplastic diseases such as rheumatoid arthritis (RA) and certain types of cancer. Although several inhibitors have been approved for medical use, their associated adverse effects limit their therapeutic use. Therefore, it is essential to search for new, safer inhibitors. In this work, we applied computer-aided approaches consisting of consensus molecular docking and molecular dynamics using the JAK2 structure as a filter of 3330 drugs approved by the Food and Drug Administration (FDA) retrieved from the ZINC20 database. The best predicted virtual hits were evaluated in an ex vivo STAT1,3 phosphorylation functional model in human lymphocytes induced by IL-6 stimulation. The docking-based consensus-scoring strategy allowed the selection of pitavastatin (PIT), eltrombopag (ELT), flavoxate (FLA), and empagliflozin (EMP) as potential JAK2 inhibitors. Their stability was confirmed by running independent molecular dynamics simulations of 200 ns in triplicate, which showed comparable stability with baricitib (BAR) and showed that hydrogen bonding is involved in their binding with key amino acids of the ATP-binding site. In the ex vivo evaluations, pitavastatin (0.5004 μM), eltrombopag (0.2548 μM), flavoxate (0.1536 μM), and empagliflozin (0.2548 μM) affected the phosphorylation of downstream STAT1 and STAT3 signaling molecules, similarly…
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