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Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family

Amir Taldaev1,2, Vladimir R Rudnev1,3, Kirill S Nikolsky1

  • 1Biobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, Russia.

Pharmaceuticals (Basel, Switzerland)
|January 21, 2022
PubMed

Insights

Upadacitinib selectively targets JAK1 for rheumatoid arthritis treatment. Molecular modeling reveals hydrogen bonds in JAKs

Area of Science:

  • Immunology and Molecular Biology
  • Rheumatology and Drug Discovery

Background:

  • Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint damage and incapacitation.
  • Cytokines, particularly interleukin-6 and IFNγ, mediate inflammatory responses via the JAK/STAT pathway.
  • Janus kinase (JAK) inhibitors have revolutionized RA therapy, with upadacitinib showing high JAK1 selectivity.

Purpose of the Study:

  • To elucidate the molecular recognition mechanism of JAK1 by upadacitinib.
  • To understand the structural basis for upadacitinib's selectivity among JAK isoforms.
  • To provide insights into drug action and pharmacophore differences in JAKs.

Main Methods:

  • Computational molecular modeling study.
  • Analysis of hydrogen bond formation characteristics.
  • Investigation of interactions within the glycine loop and hinge regions of JAKs.

Main Results:

  • Identified specific hydrogen bond characteristics with the glycine loop and hinge as key determinants of JAK selectivity.
  • Provided a detailed view of molecular interactions between upadacitinib and JAK1.
  • Highlighted differences in pharmacophore models across JAK isoforms.

Conclusions:

  • Hydrogen bond interactions in the glycine loop and hinge are critical for upadacitinib's selective inhibition of JAK1.
  • The molecular modeling study offers a mechanistic understanding of upadacitinib's action in RA.
  • Findings contribute to the rational design of selective JAK inhibitors for autoimmune diseases.
Keywords:
JAK inhibitorJanus kinasemolecular modelingrheumatoid arthritisupadacitinib

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