Abstract
Rheumatoid arthritis (RA) is a chronic disease characterized by bone joint damage and incapacitation. The mechanism underlying RA pathogenesis is autoimmunity in the connective tissue. Cytokines play an important role in the human immune system for signal transduction and in the development of inflammatory responses. Janus kinases (JAK) participate in the JAK/STAT pathway, which mediates cytokine effects, in particular interleukin 6 and IFNγ. The discovery of small molecule inhibitors of the JAK protein family has led to a revolution in RA therapy. The novel JAK inhibitor upadacitinib (RinvoqTM) has a higher selectivity for JAK1 compared to JAK2 and JAK3 in vivo. Currently, details on the molecular recognition of JAK1 by upadacitinib are not available. We found that characteristics of hydrogen bond formation with the glycine loop and hinge in JAKs define the selectivity. Our molecular modeling study could provide insight into the drug action mechanism and pharmacophore model differences in JAK isoforms.
Highlights
Janus kinases (JAKs) are tyrosine kinases associated with cytoplasmic regions of type I and II cytokine receptors
This allowed us to validate the applicability of the chosen docking path for upadacitinib docking to the active JAK sites (Table 1)
The following results were obtained: in the active site, upadacitinib formed three hydrogen bonds with JAK1, with value was observed during the alignment of the protein-ligand complexes
Summary
Janus kinases (JAKs) are tyrosine kinases associated with cytoplasmic regions of type I and II cytokine receptors. JAKs are involved in the JAK/STAT signal transducer and activator of transcription (STAT) signaling pathway, activation of the immune system, cytokine receptors, and polarization of T-helper cells [1]. This signaling pathway is regulated by a variety of factors, including suppressor of cytokine signaling, protein STAT inhibitors, and protein tyrosine phosphatase, which determine the initiation, duration, and termination of signaling cascades. Dysregulation of the JAK/STAT pathway in T-helper cells can lead to immune disorders [1].
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