Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family
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 infla...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/1/30 |
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| author | Amir Taldaev Vladimir R. Rudnev Kirill S. Nikolsky Liudmila I. Kulikova Anna L. Kaysheva |
| author_facet | Amir Taldaev Vladimir R. Rudnev Kirill S. Nikolsky Liudmila I. Kulikova Anna L. Kaysheva |
| author_sort | Amir Taldaev |
| collection | DOAJ |
| description | 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<sup>TM</sup>) 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. |
| first_indexed | 2024-03-10T00:44:54Z |
| format | Article |
| id | doaj.art-30e64dd1c02341e5890ca61160d6d568 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T00:44:54Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-30e64dd1c02341e5890ca61160d6d5682023-11-23T15:01:00ZengMDPI AGPharmaceuticals1424-82472021-12-011513010.3390/ph15010030Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein FamilyAmir Taldaev0Vladimir R. Rudnev1Kirill S. Nikolsky2Liudmila I. Kulikova3Anna L. Kaysheva4Biobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, RussiaBiobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, RussiaBiobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, RussiaBiobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, RussiaBiobanking Group, V.N. Orekhovich Institute of Biomedical Chemistry, 109028 Moscow, RussiaRheumatoid 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<sup>TM</sup>) 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.https://www.mdpi.com/1424-8247/15/1/30upadacitinibJanus kinaseJAK inhibitorrheumatoid arthritismolecular modeling |
| spellingShingle | Amir Taldaev Vladimir R. Rudnev Kirill S. Nikolsky Liudmila I. Kulikova Anna L. Kaysheva Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family Pharmaceuticals upadacitinib Janus kinase JAK inhibitor rheumatoid arthritis molecular modeling |
| title | Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family |
| title_full | Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family |
| title_fullStr | Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family |
| title_full_unstemmed | Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family |
| title_short | Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family |
| title_sort | molecular modeling insights into upadacitinib selectivity upon binding to jak protein family |
| topic | upadacitinib Janus kinase JAK inhibitor rheumatoid arthritis molecular modeling |
| url | https://www.mdpi.com/1424-8247/15/1/30 |
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