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Ruxolitinib'in COVID-19 majör proteaz enzimine ve SARS CoV-2 spike glikoproteinine karşı inhibitör aktivitesi: Bir moleküler kenetlenme çalışması.

Yıl 2023, Cilt: 8 Sayı: 2, 65 - 73, 21.12.2023

A. Demet Demirag , Sefa Çelik , Samet Arslan , Ayşen Özel , Sevim Akyüz

https://doi.org/10.56171/ojn.1134119

Öz

Ruxolitinib (C17H18N6 ), JAK1, JAK2 ve JAK3'ü inhibe eden ve tirozin kinaz inhibitör fonksiyonuna sahip bir Janus kinaz (JAK) inhibitörüdür. Miyelofibroz tedavisinde kullanım için onaylanan ilk ilaçtır. Ruxolitinib molekülünün olası konformasyonları Spartan06 programı ile PM3 yaklaşımı kullanılarak araştırılmıştır. Dihedral açılardaki değişimlerle elde edilen Ruxolitinib konformerlerinin moleküler enerjileri karşılaştırılmış ve en kararlı konformeri belirlenmiştir. Ruxolitinib'in COVID-19'un ana proteaz enziminin (Mpro ) apo/holo formlarına ve SARSCoV-2 spike glikoproteinine karşı inhibitör aktivitesini aydınlatmak için moleküler kenetlenme simülasyonları uygulanmıştır. Bağlanma afiniteleri ve bağlanma modları belirlenmiştir.

Anahtar Kelimeler

Ruxolitinib SARSCoV-2 tirozin kinaz moleküler kenetlenme

Teşekkür

İşinizi titizlikle ve hızlı bir şekilde yaptığınız için teşekkür ederim.

Kaynakça

  • 1. De Wit, E., Van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523-534.
  • 2. Laporte, M., Raeymaekers, V., Van Berwaer, R., Vandeput, J., Marchand-Casas, I., Thibaut, H. J., ... & Stevaert, A. (2021). The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways. PLoS pathogens, 17(4), e1009500.
  • 3. Pillaiyar, T., Meenakshisundaram, S., & Manickam, M. (2020). Recent discovery and development of inhibitors targeting coronaviruses. Drug discovery today, 25(4), 668-688.
  • 4. Johnson, M. C., Lyddon, T. D., Suarez, R., Salcedo, B., LePique, M., Graham, M., ... & Ritter, D. G. (2020). Optimized pseudotyping conditions for the SARS-COV-2 spike glycoprotein. Journal of virology, 94(21), e01062-20.
  • 5. Pancera, M., Zhou, T., Druz, A., Georgiev, I. S., Soto, C., Gorman, J., ... & Kwong, P. D. (2014). Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature, 514(7523), 455-461.
  • 6. Rey, F. A., & Lok, S. M. (2018). Common features of enveloped viruses and implications for immunogen design for next-generation vaccines. Cell, 172(6), 1319-1334.
  • 7. Bağca, B. G., & AVCI, Ç. B. Ruxolitinib ve etki mekanizmaları. İstanbul Bilim Üniversitesi Florence Nightingale Tıp Dergisi, 2(2), 153-157.
  • 8. Harrison, C., & Vannucchi, A. M. (2012). Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians. Therapeutic advances in hematology, 3(6), 341-354.
  • 9. Rane, S. G., & Reddy, E. P. (2000). Janus kinases: components of multiple signaling pathways. Oncogene, 19(49), 5662-5679.
  • 10. Cao, Y., Wei, J., Zou, L., Jiang, T., Wang, G., Chen, L., ... & Zhou, J. (2020). Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. Journal of Allergy and Clinical Immunology, 146(1), 137-146.
  • 11. Yeleswaram, S., Smith, P., Burn, T., Covington, M., Juvekar, A., Li, Y., ... & Langmuir, P. (2020). Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment. Clinical Immunology, 218, 108517.
  • 12. Antonopoulou, I., Sapountzaki, E., Rova, U., & Christakopoulos, P. (2022). Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds. Computational and Structural Biotechnology Journal, 20, 1306-1344.
  • 13. Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., & Soetjipto, S. (2020). Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints, 2020, 2020030226.
  • 14. Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 323(18), 1824-1836.
  • 15. Shao, Y., Molnar, L. F., Jung, Y., Kussmann, J., Ochsenfeld, C., Brown, S. T., ... & DiStasio Jr, R. A. (2006). Advances in methods and algorithms in a modern quantum chemistry program package. Physical Chemistry Chemical Physics,8(27), 3172-3191.
  • 16. Stewart, J.J.P. 1989. Optimization of parameters for semiempirical methods I. Method. J. Comput. Chem., 10(2), 209–220.
  • 17. Stewart, J.J.P. 1989. Optimization of parameters for semiempirical methods II. Applications. J. Comput. Chem., 10 (2): 221–264.
  • 18. Stewart, J.J.P. 1991. Optimization of parameters for semiempirical methods. III Extension of PM3 to Be, Mg, Zn, Ga, Ge, As, Se, Cd, In, Sn, Sb, Te, Hg, Tl, Pb, and Bi. Journal of Computational Chemistry. 12 (3), 320–341.
  • 19. Stewart, J.J.P. 2004. Optimization of parameters for semiempirical methods IV: Extension of MNDO, AM1, and PM3 to more main group elements. Journal of Molecular Modeling, 10 (2), 155–64.
  • 20. Jurcik, A.; Bednar, D.; Byska, J.; Marques, S.M.; Furmanova, K.; Daniel, L.;... Pavelka, A. CAVER Analyst 2.0: analysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectories. Bioinformatics 2018, 34, 3586-3588.
  • 21. 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.
  • 22. Zhang, B.; Zhao, Y.; Jin, Z.; Liu, X.; Yang, H.; Rao, Z. The crystal structure of COVID-19 main protease in apo form. Published Online 2020. DOI: 10.2210/pdb6M03/pdb.
  • 23. Jin, Z.;Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.;Jiang, R.; Yang, X.;You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L.W.;Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of mprofrom SARS-CoV-2 and discovery of its inhibitors. Nature2020,582, 289-293.
  • 24. Walls, A. C.; Park, Y. J.; Tortorici, M. A.; Wall, A.; McGuire, A. T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020, 181(2), 281-292.
  • 25. Sagaama, A.; Brandan, S. A.; Issa, T. B.; Issaoui, N. Searching potential antiviral candidates for the treatment of the 2019 novel coronavirus based on DFT calculations and molecular docking. Heliyon 2020, 6(8), e04640.
  • 26. Beura, S.; Chetti, P. In-silico strategies for probing chloroquine based inhibitors against SARS-CoV-2. Journal of Biomolecular Structure and Dynamics 2021, 39(10), 3747-3759.
  • 27. Veerasamy, R.; Karunakaran, R. Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach. Journal of Genetic Engineering and Biotechnology 2022, 20(1), 1-16.
  • 28. Wang, Z.; Wang, X.; Li, Y.; Lei, T.; Wang, E.; Li, D.; Kang, Y.; Zhu, F.; Hou, T. farPPI: A web server for accurate prediction of protein-ligand binding structures for small-molecule PPI inhibitors by MM/PB (GB) SA methods. Bioinformatics 2019, 35, 1777-1779.
  • 29. Hao, G.F.; Jiang, W.; Ye, Y.N.; Wu, F.X.; Zhu, X.L.; Guo, F.B.; Yang, G.F. ACFIS: A web server for fragment-based drug discovery. Nucl. Acids Res. 2016, 44, W550-W556.
  • 30. Hao, G.F.; Wang, F.; Li, H.; Zhu, X.L.; Yang, W.C.; Huang, L.S.; Wu, J.; Berry, E.A.; Yang, G.F. Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex. J. Am. Chem. Soc. 2012, 134, 11168-11176.
  • 31. Yang, J.F.; Wang, F.; Jiang, W.; Zhou, G.Y.; Li, C.Z.; Zhu, X.L.; Hao, G.; Yang, G.F. PADFrag: A database built for the exploration of bioactive fragment space for drug discovery. J. Chem. Inf. Model. 2018, 58, 1725-1730.
  • 32. Cheron, N.; Jasty, N.; Shakhnovich, E.I. OpenGrowth: An automated and rational algorithm for finding new protein ligands. J. Med. Chem. 2016, 59, 4171-4188.
  • 33. Wang, E.; Sun, H.; Wang, J.; Wang, Z.; Liu, H.; Zhang, J.Z.H.; Hou, T. End-point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design. Chem. Rev. 2019, 119, 9478–9508.

The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study

Yıl 2023, Cilt: 8 Sayı: 2, 65 - 73, 21.12.2023

A. Demet Demirag , Sefa Çelik , Samet Arslan , Ayşen Özel , Sevim Akyüz

https://doi.org/10.56171/ojn.1134119

Öz

Ruxolitinib (C17H18N6) is a Janus kinase (JAK) inhibitor that inhibits JAK1, JAK2, and JAK3 and with its tyrosine kinase inhibitor function It is the first drug approved for use in the treatment of myelofibrosis. The possible conformations of the ruxolitinib molecule were searched using PM3 technique and the Spartan06 software. The estimated molecular energies of the Ruxolitinib conformers, obtained by the variations in dihedral angles, were compared, and the most stable conformer was determined. To enlighten the inhibitory activity of Ruxolitinib agaist the apo (PDB ID: 6M03) and holo (PDB ID: 6LU7) forms of the main protease enzyme (Mpro) of COVID-19 and the SARSCoV-2 spike glycoprotein (PDB ID: 6VXX), molecular docking simulations were performed. The binding affinities and binding modes were determined. The binding free energies of ruxolitinib and 6M03, 6LU7, 6VXX targets calculated by the combination of Molecular Mechanics/Generalized Born Surface Area (MMGBSA) and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methods {MM/PB(GB)SA approach}, were found to be -22.24, -19.96 and -22.44 kcal/mol, respectively.

Anahtar Kelimeler

Ruxolitinib SARSCoV-2 tyrosine kinase molecular docking

Kaynakça

  • 1. De Wit, E., Van Doremalen, N., Falzarano, D., & Munster, V. J. (2016). SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology, 14(8), 523-534.
  • 2. Laporte, M., Raeymaekers, V., Van Berwaer, R., Vandeput, J., Marchand-Casas, I., Thibaut, H. J., ... & Stevaert, A. (2021). The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways. PLoS pathogens, 17(4), e1009500.
  • 3. Pillaiyar, T., Meenakshisundaram, S., & Manickam, M. (2020). Recent discovery and development of inhibitors targeting coronaviruses. Drug discovery today, 25(4), 668-688.
  • 4. Johnson, M. C., Lyddon, T. D., Suarez, R., Salcedo, B., LePique, M., Graham, M., ... & Ritter, D. G. (2020). Optimized pseudotyping conditions for the SARS-COV-2 spike glycoprotein. Journal of virology, 94(21), e01062-20.
  • 5. Pancera, M., Zhou, T., Druz, A., Georgiev, I. S., Soto, C., Gorman, J., ... & Kwong, P. D. (2014). Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Nature, 514(7523), 455-461.
  • 6. Rey, F. A., & Lok, S. M. (2018). Common features of enveloped viruses and implications for immunogen design for next-generation vaccines. Cell, 172(6), 1319-1334.
  • 7. Bağca, B. G., & AVCI, Ç. B. Ruxolitinib ve etki mekanizmaları. İstanbul Bilim Üniversitesi Florence Nightingale Tıp Dergisi, 2(2), 153-157.
  • 8. Harrison, C., & Vannucchi, A. M. (2012). Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians. Therapeutic advances in hematology, 3(6), 341-354.
  • 9. Rane, S. G., & Reddy, E. P. (2000). Janus kinases: components of multiple signaling pathways. Oncogene, 19(49), 5662-5679.
  • 10. Cao, Y., Wei, J., Zou, L., Jiang, T., Wang, G., Chen, L., ... & Zhou, J. (2020). Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. Journal of Allergy and Clinical Immunology, 146(1), 137-146.
  • 11. Yeleswaram, S., Smith, P., Burn, T., Covington, M., Juvekar, A., Li, Y., ... & Langmuir, P. (2020). Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment. Clinical Immunology, 218, 108517.
  • 12. Antonopoulou, I., Sapountzaki, E., Rova, U., & Christakopoulos, P. (2022). Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds. Computational and Structural Biotechnology Journal, 20, 1306-1344.
  • 13. Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S., & Soetjipto, S. (2020). Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints, 2020, 2020030226.
  • 14. Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 323(18), 1824-1836.
  • 15. Shao, Y., Molnar, L. F., Jung, Y., Kussmann, J., Ochsenfeld, C., Brown, S. T., ... & DiStasio Jr, R. A. (2006). Advances in methods and algorithms in a modern quantum chemistry program package. Physical Chemistry Chemical Physics,8(27), 3172-3191.
  • 16. Stewart, J.J.P. 1989. Optimization of parameters for semiempirical methods I. Method. J. Comput. Chem., 10(2), 209–220.
  • 17. Stewart, J.J.P. 1989. Optimization of parameters for semiempirical methods II. Applications. J. Comput. Chem., 10 (2): 221–264.
  • 18. Stewart, J.J.P. 1991. Optimization of parameters for semiempirical methods. III Extension of PM3 to Be, Mg, Zn, Ga, Ge, As, Se, Cd, In, Sn, Sb, Te, Hg, Tl, Pb, and Bi. Journal of Computational Chemistry. 12 (3), 320–341.
  • 19. Stewart, J.J.P. 2004. Optimization of parameters for semiempirical methods IV: Extension of MNDO, AM1, and PM3 to more main group elements. Journal of Molecular Modeling, 10 (2), 155–64.
  • 20. Jurcik, A.; Bednar, D.; Byska, J.; Marques, S.M.; Furmanova, K.; Daniel, L.;... Pavelka, A. CAVER Analyst 2.0: analysis and visualization of channels and tunnels in protein structures and molecular dynamics trajectories. Bioinformatics 2018, 34, 3586-3588.
  • 21. 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.
  • 22. Zhang, B.; Zhao, Y.; Jin, Z.; Liu, X.; Yang, H.; Rao, Z. The crystal structure of COVID-19 main protease in apo form. Published Online 2020. DOI: 10.2210/pdb6M03/pdb.
  • 23. Jin, Z.;Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.;Jiang, R.; Yang, X.;You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L.W.;Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of mprofrom SARS-CoV-2 and discovery of its inhibitors. Nature2020,582, 289-293.
  • 24. Walls, A. C.; Park, Y. J.; Tortorici, M. A.; Wall, A.; McGuire, A. T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020, 181(2), 281-292.
  • 25. Sagaama, A.; Brandan, S. A.; Issa, T. B.; Issaoui, N. Searching potential antiviral candidates for the treatment of the 2019 novel coronavirus based on DFT calculations and molecular docking. Heliyon 2020, 6(8), e04640.
  • 26. Beura, S.; Chetti, P. In-silico strategies for probing chloroquine based inhibitors against SARS-CoV-2. Journal of Biomolecular Structure and Dynamics 2021, 39(10), 3747-3759.
  • 27. Veerasamy, R.; Karunakaran, R. Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach. Journal of Genetic Engineering and Biotechnology 2022, 20(1), 1-16.
  • 28. Wang, Z.; Wang, X.; Li, Y.; Lei, T.; Wang, E.; Li, D.; Kang, Y.; Zhu, F.; Hou, T. farPPI: A web server for accurate prediction of protein-ligand binding structures for small-molecule PPI inhibitors by MM/PB (GB) SA methods. Bioinformatics 2019, 35, 1777-1779.
  • 29. Hao, G.F.; Jiang, W.; Ye, Y.N.; Wu, F.X.; Zhu, X.L.; Guo, F.B.; Yang, G.F. ACFIS: A web server for fragment-based drug discovery. Nucl. Acids Res. 2016, 44, W550-W556.
  • 30. Hao, G.F.; Wang, F.; Li, H.; Zhu, X.L.; Yang, W.C.; Huang, L.S.; Wu, J.; Berry, E.A.; Yang, G.F. Computational discovery of picomolar Qo site inhibitors of cytochrome bc1 complex. J. Am. Chem. Soc. 2012, 134, 11168-11176.
  • 31. Yang, J.F.; Wang, F.; Jiang, W.; Zhou, G.Y.; Li, C.Z.; Zhu, X.L.; Hao, G.; Yang, G.F. PADFrag: A database built for the exploration of bioactive fragment space for drug discovery. J. Chem. Inf. Model. 2018, 58, 1725-1730.
  • 32. Cheron, N.; Jasty, N.; Shakhnovich, E.I. OpenGrowth: An automated and rational algorithm for finding new protein ligands. J. Med. Chem. 2016, 59, 4171-4188.
  • 33. Wang, E.; Sun, H.; Wang, J.; Wang, Z.; Liu, H.; Zhang, J.Z.H.; Hou, T. End-point binding free energy calculation with MM/PBSA and MM/GBSA: Strategies and applications in drug design. Chem. Rev. 2019, 119, 9478–9508.
Toplam 33 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Mühendislik
Bölüm Araştırma Makalesi
Yazarlar

A. Demet Demirag 0000-0002-9609-9150

Sefa Çelik 0000-0001-6216-1297

Samet Arslan 0000-0003-2164-3905

Ayşen Özel 0000-0002-8680-8830

Sevim Akyüz 0000-0003-3313-6927

Yayımlanma Tarihi 21 Aralık 2023
Gönderilme Tarihi 23 Haziran 2022
Yayımlandığı Sayı Yıl 2023 Cilt: 8 Sayı: 2

Kaynak Göster

APA Demirag, A. D., Çelik, S., Arslan, S., Özel, A., vd. (2023). The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study. Open Journal of Nano, 8(2), 65-73. https://doi.org/10.56171/ojn.1134119
AMA Demirag AD, Çelik S, Arslan S, Özel A, Akyüz S. The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study. OJN. Aralık 2023;8(2):65-73. doi:10.56171/ojn.1134119
Chicago Demirag, A. Demet, Sefa Çelik, Samet Arslan, Ayşen Özel, ve Sevim Akyüz. “The Inhibitory Activity of Ruxolitinib Against COVID-19 Major Protease Enzyme and SARS CoV-2 Spike Glycoprotein: A Molecular Docking Study”. Open Journal of Nano 8, sy. 2 (Aralık 2023): 65-73. https://doi.org/10.56171/ojn.1134119.
EndNote Demirag AD, Çelik S, Arslan S, Özel A, Akyüz S (01 Aralık 2023) The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study. Open Journal of Nano 8 2 65–73.
IEEE A. D. Demirag, S. Çelik, S. Arslan, A. Özel, ve S. Akyüz, “The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study”, OJN, c. 8, sy. 2, ss. 65–73, 2023, doi: 10.56171/ojn.1134119.
ISNAD Demirag, A. Demet vd. “The Inhibitory Activity of Ruxolitinib Against COVID-19 Major Protease Enzyme and SARS CoV-2 Spike Glycoprotein: A Molecular Docking Study”. Open Journal of Nano 8/2 (Aralık 2023), 65-73. https://doi.org/10.56171/ojn.1134119.
JAMA Demirag AD, Çelik S, Arslan S, Özel A, Akyüz S. The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study. OJN. 2023;8:65–73.
MLA Demirag, A. Demet vd. “The Inhibitory Activity of Ruxolitinib Against COVID-19 Major Protease Enzyme and SARS CoV-2 Spike Glycoprotein: A Molecular Docking Study”. Open Journal of Nano, c. 8, sy. 2, 2023, ss. 65-73, doi:10.56171/ojn.1134119.
Vancouver Demirag AD, Çelik S, Arslan S, Özel A, Akyüz S. The inhibitory activity of Ruxolitinib against COVID-19 major protease enzyme and SARS CoV-2 spike glycoprotein: A molecular docking study. OJN. 2023;8(2):65-73.
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