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

Year 2023, , 65 - 73, 21.12.2023

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

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

Abstract

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.

Keywords

Ruxolitinib, SARSCoV-2, tirozin kinaz, moleküler kenetlenme

Thanks

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

Abstract

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.

Keywords

Ruxolitinib, SARSCoV-2, tyrosine kinase, molecular docking

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