ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2026-3-87-92ssmu-6605Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSКомпьютерное моделирование взаимодействия киназы JAK3 с ксантотоксиномComputer Simulation of the Interaction between Janus Kinase 3 (JAK3) and Xanthotoxinhttps://orcid.org/0000-0001-6077-0347ЧасовскихН. Ю.ChasovskikhN. Yu.

Часовских Наталия Юрьевна д-р мед. наук, доцент, зав. кафедрой медицинской и биологической кибернетики

634050, г. Томск, Московский тракт, 2

2 Moskovsky trakt, 634050 Tomsk

chasovskih.ny@ssmu.ruhttps://orcid.org/0000-0003-4731-8449ШестаковаЕ. Е.ShestakovaE. E.

Шестакова Евгения Евгеньевна ст. преподаватель, кафедра медицинской и биологической кибернетики

634050, г. Томск, Московский тракт, 2

2 Moskovsky trakt, 634050 Tomsk

chizik.ee@ssmu.ruСибирский государственный медицинский университет (СибГМУ)РоссияSiberian State Medical UniversityRussian Federation2026011020262538792Copyright © Часовских Н.Ю., Шестакова Е.Е., 20262026Часовских Н.Ю., Шестакова Е.Е.Chasovskikh N.Y., Shestakova E.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/6605

Цель исследования провести компьютерное моделирование и оценить взаимодействие киназы JAK3 с ксантотоксином.

Материалы и методы

Материалы и методы. 3D-cтруктуры киназы JAK3 (PDB ID: 5LWM) и ксантотоксина PubChem (PubChem ID: 4114) были получены из банка данных белков PDB и базы данных химических соединений и смесей соответственно. На этапе подготовки структуры киназы к проведению молекулярного докинга применяли PyMOL v. 2.5, для конвертации ксантотоксина в формат .pdb использовали OpenBabel. Молекулярный до­кинг выполняли в AutoDock Vina, молекулярно-динамическое моделирование в GROMACS 2023.3. Для построения топологии белка использовали силовое поле CHARMM 36, для топологии лиганда сервер CHARMM General Force Field (CGenFF). Для анализа результатов применяли программы Xmgrace и PyMOL.

Результаты

Результаты. В результате проведенного молекулярного докинга киназы JAK3 и ксантотоксина получен стабильный комплекс с энергией связывания -7,043 ккал/моль. Выявлены аминокислотные остатки ки­назы JAK3, участвующие в межмолекулярном взаимодействии: лейцин в позициях 828 (LEU828) и 905 (LEU905). Устойчивость комплекса, полученного в результате докинга, подтверждена результатами симу­ляции молекулярной динамики. Проведенная молекулярная динамика показала, что комплекс киназы JAK3 сохраняет свою структуру на протяжении всего моделирования в присутствии ксантотоксина, система на­ходится в устойчивом состоянии.

Заключение

Заключение. Полученные данные свидетельствуют о возможной роли ксантотоксина в реализации програм­мируемой гибели клеток и могут быть использованы для дальнейших экспериментальных исследований.

Aim

Aim. To perform computer modeling and evaluate the interaction of Janus Kinase 3 (JAK3) with xanthotoxin.

Materials and methods

Materials and methods. The 3D structures of JAK3 (PDB ID: 5LWM) and xanthotoxin PubChem (PubChem ID: 4114) were obtained from the Protein Data Bank (PDB) and the Chemical Compounds and Mixtures Database (CCM), respectively. PyMOL v. 2.5 was used to prepare the kinase structure for molecular docking, and OpenBabel was used to convert xanthotoxin to .pdb format. Molecular docking was performed using AutoDock Vina, and molecular dynamics simulations were performed using GROMACS 2023.3. The CHARMM36 force field was used to construct protein topology, and the CHARMM General Force Field (CGenFF) server was used for ligand topology. Xmgrace and PyMOL were used to analyze the results.

Results

Results. Molecular docking of JAK3 and xanthotoxin yielded a stable complex with a binding energy of 7.043 kcal/mol. The amino acid residues of JAK3 involved in the intermolecular interaction were identified: leucine at position 828 (LEU828) and at position 905 (LEU905). The stability of the docked complex was confirmed by molecular dynamics simulations. Molecular dynamics simulations showed that the JAK3 complex maintained its structure throughout the simulation in the presence of xanthotoxin; the system reached an equilibrium state.

Conclusion

Conclusion. These data suggest a possible role for xanthotoxin in programmed cell death and can be used for further experimental studies.

молекулярный докингмолекулярная динамикакиназа JAK3ксантотоксинапоптозmolecular dockingmolecular dynamicsJAK3xanthotoxinapoptosisReferencesЕстественное движение населения Российской Федерации за 2023 год (cтатистический бюллетень). М.: Росстат, 2024. URL: http://www.rosstat.gov.ruЕстественное движение населения Российской Федерации за 2023 год (cтатистический бюллетень). М.: Росстат, 2024. URL: http://www.rosstat.gov.ruГлухов А.И., Грызунова Г.К., Усай Л.И., Алейникова Т.Л., Черникова Н.В., Бурт А.Ю. Роль апоптоза в патогенезе некоторых критических состояний. Общая реаниматология. 2019;15(2):79–98. DOI: 10.15360/1813-9779-2019-2-79-98.Глухов А.И., Грызунова Г.К., Усай Л.И., Алейникова Т.Л., Черникова Н.В., Бурт А.Ю. Роль апоптоза в патогенезе некоторых критических состояний. Общая реаниматология. 2019;15(2):79–98. DOI: 10.15360/1813-9779-2019-2-79-98.Часовских Н.Ю., Рязанцева Н.В., Новицкий В.В. Апоптоз и окислительный стресс. Томск: Печатная мануфактура, 2009:148.Часовских Н.Ю., Рязанцева Н.В., Новицкий В.В. Апоптоз и окислительный стресс. Томск: Печатная мануфактура, 2009:148.Elmore S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 2007;35(4):495–516. DOI: 10.1080/01926230701320337.Elmore S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 2007;35(4):495–516. DOI: 10.1080/01926230701320337.Gao S., Zhan L., Yang Z., Shi R., Li H., Xia Z. et al. Remote limb ischaemic postconditioning protects against myocardial ischaemia/reperfusion injury in mice: activation of JAK/ STAT3-mediated Nrf2-antioxidant signalling. Cell Physiol. Biochem. 2017;43(3):1140–1151. DOI: 10.1159/000481755.Gao S., Zhan L., Yang Z., Shi R., Li H., Xia Z. et al. Remote limb ischaemic postconditioning protects against myocardial ischaemia/reperfusion injury in mice: activation of JAK/ STAT3-mediated Nrf2-antioxidant signalling. Cell Physiol. Biochem. 2017;43(3):1140–1151. DOI: 10.1159/000481755.Rawlings J.S., Rosler K.M., Harrison D.A. The JAK/STAT signaling pathway. J. Cell Sci. 2004;117(Pt 8):1281–1283. DOI: 10.1242/jcs.00963.Rawlings J.S., Rosler K.M., Harrison D.A. The JAK/STAT signaling pathway. J. Cell Sci. 2004;117(Pt 8):1281–1283. DOI: 10.1242/jcs.00963.Morris R., Kershaw N.J., Babon J.J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018;27(12):1984–2009. DOI: 10.1002/pro.3519.Morris R., Kershaw N.J., Babon J.J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018;27(12):1984–2009. DOI: 10.1002/pro.3519.Ahmed S., Khan H., Aschner M., Mirzae H., Küpeli Akkol E., Capasso R. Anticancer potential of furanocoumarins: mechanistic and therapeutic aspects. Int. J. Mol. Sci. 2020;21(16):5622. DOI: 10.3390/ijms21165622.Ahmed S., Khan H., Aschner M., Mirzae H., Küpeli Akkol E., Capasso R. Anticancer potential of furanocoumarins: mechanistic and therapeutic aspects. Int. J. Mol. Sci. 2020;21(16):5622. DOI: 10.3390/ijms21165622.Kubrak T., Czop M., Kołodziej P., Ziaja-Sołtys M., Bogucki J., Makuch-Kocka A. et al. The effect of furanocoumarin derivatives on induction of apoptosis and multidrug resistance in human leukemic cells. Molecules. 2019;24(9):1824. DOI: 10.3390/molecules24091824.Kubrak T., Czop M., Kołodziej P., Ziaja-Sołtys M., Bogucki J., Makuch-Kocka A. et al. The effect of furanocoumarin derivatives on induction of apoptosis and multidrug resistance in human leukemic cells. Molecules. 2019;24(9):1824. DOI: 10.3390/molecules24091824.Issa M.Y., Elshal M.F., Fathallah N., Abdelkawy M.A., Bishr M., Salama O. et al. Potential anticancer activity of the furanocoumarin derivative xanthotoxin isolated from Ammi majus L. Fruits: in vitro and in silico studies. Molecules. 2022;27(3):943. DOI: 10.3390/molecules27030943.Issa M.Y., Elshal M.F., Fathallah N., Abdelkawy M.A., Bishr M., Salama O. et al. Potential anticancer activity of the furanocoumarin derivative xanthotoxin isolated from Ammi majus L. Fruits: in vitro and in silico studies. Molecules. 2022;27(3):943. DOI: 10.3390/molecules27030943.Wu A., Lu J., Zhong G., Lu L., Qu Y., Zhang C. Xanthotoxin (8-methoxypsoralen): A review of its chemistry, pharmacology, pharmacokinetics, and toxicity. Phytother. Res. 2022;36(10):3805–3832. DOI: 10.1002/ptr.7577.Wu A., Lu J., Zhong G., Lu L., Qu Y., Zhang C. Xanthotoxin (8-methoxypsoralen): A review of its chemistry, pharmacology, pharmacokinetics, and toxicity. Phytother. Res. 2022;36(10):3805–3832. DOI: 10.1002/ptr.7577.Lee Y., Hyun C.G. Anti-inflammatory effects of psoralen derivatives on RAW264.7 cells via regulation of the NF-κB and MAPK signaling pathways. Int. J. Mol. Sci. 2022;23(10):5813. DOI: 10.3390/ijms23105813.Lee Y., Hyun C.G. Anti-inflammatory effects of psoralen derivatives on RAW264.7 cells via regulation of the NF-κB and MAPK signaling pathways. Int. J. Mol. Sci. 2022;23(10):5813. DOI: 10.3390/ijms23105813.Sumorek-Wiadro J., Zając A., Maciejczyk A., Jakubowicz-Gil J. Furanocoumarins in anticancer therapy – for and against. Fitoterapia. 2020;142:104492. DOI: 10.1016/j.fitote.2020.104492.Sumorek-Wiadro J., Zając A., Maciejczyk A., Jakubowicz-Gil J. Furanocoumarins in anticancer therapy – for and against. Fitoterapia. 2020;142:104492. DOI: 10.1016/j.fitote.2020.104492.Lee S.B., Lee W.S., Shin J.S., Jang D.S., Lee K.T. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int. Immunopharmacol. 2017;49:21–29. DOI: 10.1016/j.intimp.2017.05.021.Lee S.B., Lee W.S., Shin J.S., Jang D.S., Lee K.T. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int. Immunopharmacol. 2017;49:21–29. DOI: 10.1016/j.intimp.2017.05.021.Kurach L., Kulczycka-Mamona S., Kowalczyk J., Skalicka-Wozniak K., Boguszewska-Czubara A., El Sayed N. et al. Mechanisms of the procognitive effects of xanthotoxin and umbelliferone on LPS-induced amnesia in mice. Int. J. Mol. Sci. 2021;22(4):1779. DOI: 10.3390/ijms22041779.Kurach L., Kulczycka-Mamona S., Kowalczyk J., Skalicka-Wozniak K., Boguszewska-Czubara A., El Sayed N. et al. Mechanisms of the procognitive effects of xanthotoxin and umbelliferone on LPS-induced amnesia in mice. Int. J. Mol. Sci. 2021;22(4):1779. DOI: 10.3390/ijms22041779.Perri M.R., Pellegrino M., Aquaro S., Cavaliere F., Lupia C., Uzunov D. et al. Cachrys spp. from southern Italy: phytochemical characterization and JAK/STAT signaling pathway inhibition. Plants. 2022;11(21);2913. DOI: 10.3390/plants11212913.Perri M.R., Pellegrino M., Aquaro S., Cavaliere F., Lupia C., Uzunov D. et al. Cachrys spp. from southern Italy: phytochemical characterization and JAK/STAT signaling pathway inhibition. Plants. 2022;11(21);2913. DOI: 10.3390/plants11212913.Lionta E., Spyrou G., Vassilatis D.K., Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem. 2014;14(16):1923–1938. DOI: 10.2174/1568026614666140929124445.Lionta E., Spyrou G., Vassilatis D.K., Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem. 2014;14(16):1923–1938. DOI: 10.2174/1568026614666140929124445.Pagadala N.S., Syed K., Tuszynski J. Software for molecular docking: a review. Biophys. Rev. 2017;9(2):91–102. DOI: 10.1007/s12551-016-0247-1.Pagadala N.S., Syed K., Tuszynski J. Software for molecular docking: a review. Biophys. Rev. 2017;9(2):91–102. DOI: 10.1007/s12551-016-0247-1.Gautam S., Pathak S., Dubey S.H. The Role of Molecular Docking in Modern Drug Discovery and Development: A Comprehensive Review. Journal of Drug Discovery and Health Sciences. 2024;1(3):129–137. DOI: 10.21590/ijddhs.01.03.02.Gautam S., Pathak S., Dubey S.H. The Role of Molecular Docking in Modern Drug Discovery and Development: A Comprehensive Review. Journal of Drug Discovery and Health Sciences. 2024;1(3):129–137. DOI: 10.21590/ijddhs.01.03.02.Sinha S., Tam B., Wang S.M. Applications of Molecular Dynamics Simulation in Protein Study. Membranes (Basel). 2022;12(9):844. DOI: 10.3390/membranes12090844.Sinha S., Tam B., Wang S.M. Applications of Molecular Dynamics Simulation in Protein Study. Membranes (Basel). 2022;12(9):844. DOI: 10.3390/membranes12090844.Faris A., Cacciatore I., Ibrahim I.M., Al Mughram M.H., Hadni H., Tabti K. et al. In silico computational drug discovery: a Monte Carlo approach for developing a novel JAK3 inhibitors. J. Biomol. Struct. Dyn. 2024;42(22):12548–12570. DOI: 10.1080/07391102.2023.2270709.Faris A., Cacciatore I., Ibrahim I.M., Al Mughram M.H., Hadni H., Tabti K. et al. In silico computational drug discovery: a Monte Carlo approach for developing a novel JAK3 inhibitors. J. Biomol. Struct. Dyn. 2024;42(22):12548–12570. DOI: 10.1080/07391102.2023.2270709.Wei J., Pan Y., Shen Z., Shen L., Xu L., Yu W. et al. A hybrid energy-based and AI-based screening approach for the discovery of novel inhibitors of JAK3. Front. Med (Lausanne). 2023;10:1182227. DOI: 10.3389/fmed.2023.1182227.Wei J., Pan Y., Shen Z., Shen L., Xu L., Yu W. et al. A hybrid energy-based and AI-based screening approach for the discovery of novel inhibitors of JAK3. Front. Med (Lausanne). 2023;10:1182227. DOI: 10.3389/fmed.2023.1182227.Jain D., Udhwani T., Sharma S., Gandhe A., Reddy P.B., Nayarisseri A. et al. Design of novel JAK3 inhibitors towards rheumatoid arthritis using molecular docking analysis. Bioinformation. 2019;15(2):68–78. DOI: 10.6026/97320630015068.Jain D., Udhwani T., Sharma S., Gandhe A., Reddy P.B., Nayarisseri A. et al. Design of novel JAK3 inhibitors towards rheumatoid arthritis using molecular docking analysis. Bioinformation. 2019;15(2):68–78. DOI: 10.6026/97320630015068.Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H. et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235–242. DOI: 10.1093/nar/28.1.235.Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H. et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235–242. DOI: 10.1093/nar/28.1.235.Kim S., Chen J., Cheng T., Gindulyte A., He J., He S. et al. PubChem 2025 update. Nucleic Acids Res. 2025;53(D1):D1516– D1525. DOI: 10.1093/nar/gkae1059.Kim S., Chen J., Cheng T., Gindulyte A., He J., He S. et al. PubChem 2025 update. Nucleic Acids Res. 2025;53(D1):D1516– D1525. DOI: 10.1093/nar/gkae1059.Schrödinger L., DeLano W. PyMOL. 2020. URL: http://www.pymol.org/pymolSchrödinger L., DeLano W. PyMOL. 2020. URL: http://www.pymol.org/pymolO’Boyle N.M., Banck M., James C.A., Morley C., Vandermeersch T., Hutchison G.R. Open Babel: An open chemical toolbox. J. Cheminform. 2011;3:33. DOI: 10.1186/1758-2946-3-33.O’Boyle N.M., Banck M., James C.A., Morley C., Vandermeersch T., Hutchison G.R. Open Babel: An open chemical toolbox. J. Cheminform. 2011;3:33. DOI: 10.1186/1758-2946-3-33.Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010;31:455–461. DOI: 10.1002/jcc.21334.Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010;31:455–461. DOI: 10.1002/jcc.21334.Abraham M.J., Murtola T., Schulz R., Páll S., Smith J.C., Hess B. et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25. DOI: 10.1016/j.softx.2015.06.001.Abraham M.J., Murtola T., Schulz R., Páll S., Smith J.C., Hess B. et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25. DOI: 10.1016/j.softx.2015.06.001.Vanommeslaeghe K., Hatcher E., Acharya C., Kundu S., Zhong S., Shim J. et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 2010;31(4):671–690. DOI: 10.1002/jcc.21367.Vanommeslaeghe K., Hatcher E., Acharya C., Kundu S., Zhong S., Shim J. et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 2010;31(4):671–690. DOI: 10.1002/jcc.21367.Vaught A. Graphing with Gnuplot and Xmgr: two graphing packages available under Linux. Linux J. 1996;1996:7.Vaught A. Graphing with Gnuplot and Xmgr: two graphing packages available under Linux. Linux J. 1996;1996:7.Nairismägi M.L., Gerritsen M.E., Li Z.M., Wijaya G.C., Chia B.K.H., Laurensia Y. et al. Oncogenic activation of JAK3- STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia. 2018;32(5):1147–1156. DOI: 10.1038/s41375-017-0004-x.Nairismägi M.L., Gerritsen M.E., Li Z.M., Wijaya G.C., Chia B.K.H., Laurensia Y. et al. Oncogenic activation of JAK3- STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia. 2018;32(5):1147–1156. DOI: 10.1038/s41375-017-0004-x.Kim S.M., Lee J.H., Sethi G., Kim C., Baek S.H., Nam D. et al. Bergamottin, a natural furanocoumarin obtained from grapefruit juice induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells. Cancer Lett. 20141;354(1):153–163. DOI: 10.1016/j.canlet.2014.08.002.Kim S.M., Lee J.H., Sethi G., Kim C., Baek S.H., Nam D. et al. Bergamottin, a natural furanocoumarin obtained from grapefruit juice induces chemosensitization and apoptosis through the inhibition of STAT3 signaling pathway in tumor cells. Cancer Lett. 20141;354(1):153–163. DOI: 10.1016/j.canlet.2014.08.002.Shi X., Lai Y., Liu W., Zhang X., Cang Y. Natural compound Byakangelicin suppresses breast tumor growth and motility by regulating SHP-1/JAK2/STAT3 signal pathway. Biochem. Biophys. Res. Commun. 2024;706:149758. DOI: 10.1016/j.bbrc.2024.149758.Shi X., Lai Y., Liu W., Zhang X., Cang Y. Natural compound Byakangelicin suppresses breast tumor growth and motility by regulating SHP-1/JAK2/STAT3 signal pathway. Biochem. Biophys. Res. Commun. 2024;706:149758. DOI: 10.1016/j.bbrc.2024.149758.

The authors declare that there are no conflicts of interest present.