AI Article Synopsis
- Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint damage and significant disability, largely driven by cytokines and the JAK/STAT signaling pathway.
- The development of small molecule inhibitors targeting the JAK family has transformed RA treatment, with upadacitinib (Rinvoq) being a notable option due to its selectivity for JAK1 over JAK2 and JAK3.
- Research indicates that the binding characteristics of upadacitinib with JAK1 through hydrogen bonds provide insights into its mechanism of action and how it differs among various JAK isoforms.
Article 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 (Rinvoq) 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778839 | PMC |
| http://dx.doi.org/10.3390/ph15010030 | DOI Listing |
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