Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib
Rheumatoid arthritis belongs to the group of chronic systemic autoimmune diseases characterized by the development of destructive synovitis and extra-articular manifestations. Cytokines regulate a wide range of inflammatory processes involved in the pathogenesis of rheumatoid arthritis and contribut...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/18/10466 |
| _version_ | 1797487412145815552 |
|---|---|
| author | Maxim Kondratyev Vladimir R. Rudnev Kirill S. Nikolsky Alexander A. Stepanov Denis V. Petrovsky Liudmila I. Kulikova Arthur T. Kopylov Kristina A. Malsagova Anna L. Kaysheva |
| author_facet | Maxim Kondratyev Vladimir R. Rudnev Kirill S. Nikolsky Alexander A. Stepanov Denis V. Petrovsky Liudmila I. Kulikova Arthur T. Kopylov Kristina A. Malsagova Anna L. Kaysheva |
| author_sort | Maxim Kondratyev |
| collection | DOAJ |
| description | Rheumatoid arthritis belongs to the group of chronic systemic autoimmune diseases characterized by the development of destructive synovitis and extra-articular manifestations. Cytokines regulate a wide range of inflammatory processes involved in the pathogenesis of rheumatoid arthritis and contribute to the induction of autoimmunity and chronic inflammation. Janus-associated kinase (JAK) and signal transducer and activator of transcription (STAT) proteins mediate cell signaling from cytokine receptors, and are involved in the pathogenesis of autoimmune and inflammatory diseases. Targeted small-molecule drugs that inhibit the functional activity of JAK proteins are used in clinical practice for the treatment of rheumatoid arthritis. In our study, we modeled the interactions of the small-molecule drug ruxolitinib with JAK1 and JAK2 isoforms and determined the binding selectivity using molecular docking. Molecular modeling data show that ruxolitinib selectively binds the JAK1 and JAK2 isoforms with a binding affinity of −8.3 and −8.0 kcal/mol, respectively. The stabilization of ligands in the cavity of kinases occurs primarily through hydrophobic interactions. The amino acid residues of the protein globules of kinases that are responsible for the correct positioning of the drug ruxolitinib and its retention have been determined. |
| first_indexed | 2024-03-09T23:47:17Z |
| format | Article |
| id | doaj.art-f42c3768f047493cadfd6f46b9c87191 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:47:17Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f42c3768f047493cadfd6f46b9c871912023-11-23T16:42:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181046610.3390/ijms231810466Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor RuxolitinibMaxim Kondratyev0Vladimir R. Rudnev1Kirill S. Nikolsky2Alexander A. Stepanov3Denis V. Petrovsky4Liudmila I. Kulikova5Arthur T. Kopylov6Kristina A. Malsagova7Anna L. Kaysheva8Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaBiobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, RussiaRheumatoid arthritis belongs to the group of chronic systemic autoimmune diseases characterized by the development of destructive synovitis and extra-articular manifestations. Cytokines regulate a wide range of inflammatory processes involved in the pathogenesis of rheumatoid arthritis and contribute to the induction of autoimmunity and chronic inflammation. Janus-associated kinase (JAK) and signal transducer and activator of transcription (STAT) proteins mediate cell signaling from cytokine receptors, and are involved in the pathogenesis of autoimmune and inflammatory diseases. Targeted small-molecule drugs that inhibit the functional activity of JAK proteins are used in clinical practice for the treatment of rheumatoid arthritis. In our study, we modeled the interactions of the small-molecule drug ruxolitinib with JAK1 and JAK2 isoforms and determined the binding selectivity using molecular docking. Molecular modeling data show that ruxolitinib selectively binds the JAK1 and JAK2 isoforms with a binding affinity of −8.3 and −8.0 kcal/mol, respectively. The stabilization of ligands in the cavity of kinases occurs primarily through hydrophobic interactions. The amino acid residues of the protein globules of kinases that are responsible for the correct positioning of the drug ruxolitinib and its retention have been determined.https://www.mdpi.com/1422-0067/23/18/10466ruxolitinibJAK inhibitorrheumatoid arthritismolecular modeling |
| spellingShingle | Maxim Kondratyev Vladimir R. Rudnev Kirill S. Nikolsky Alexander A. Stepanov Denis V. Petrovsky Liudmila I. Kulikova Arthur T. Kopylov Kristina A. Malsagova Anna L. Kaysheva Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib International Journal of Molecular Sciences ruxolitinib JAK inhibitor rheumatoid arthritis molecular modeling |
| title | Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib |
| title_full | Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib |
| title_fullStr | Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib |
| title_full_unstemmed | Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib |
| title_short | Atomic Simulation of the Binding of JAK1 and JAK2 with the Selective Inhibitor Ruxolitinib |
| title_sort | atomic simulation of the binding of jak1 and jak2 with the selective inhibitor ruxolitinib |
| topic | ruxolitinib JAK inhibitor rheumatoid arthritis molecular modeling |
| url | https://www.mdpi.com/1422-0067/23/18/10466 |
| work_keys_str_mv | AT maximkondratyev atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT vladimirrrudnev atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT kirillsnikolsky atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT alexanderastepanov atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT denisvpetrovsky atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT liudmilaikulikova atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT arthurtkopylov atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT kristinaamalsagova atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib AT annalkaysheva atomicsimulationofthebindingofjak1andjak2withtheselectiveinhibitorruxolitinib |