ANKİLOZAN SPONDİLİT TEDAVİSİNDE İLAÇ YENİDEN YERLEŞTİRME YAKLAŞIMI

Amaç: Bu çalışmada, AS'de inflamasyonun önlenmesinde önemli bir hedef olan IL-17 reseptörünü inhibe eden FDA onaylı bir molekülün ilaç yeniden konumlandırma yaklaşımı kullanılarak belirlenmesi amaçlanmıştır. Gereç ve Yöntem: “Drug-Gene Interaction” veritabanı kullanılarak AS'de etkin HLA-B genine özgü 18 molekül belirlenmiştir. Ardından IL-17'nin 3D yapısına RSCB veri tabanından ulaşılmıştır. Bağlanma paketinin belirlenmesi için I) Kör kenetlenme II) “Computed Atlas of Surface Topography of Proteins” web aracı kullanılmıştır. Belirlenen bağlanma paketleri çevresindeki grid kutuları kullanılarak IL-17'nin bilinen inhibitörü rhodomyrtone ile IL-17 arasındaki etkileşim moleküler doking ile belirlenmiştir. Buna göre seçilen grid kutusu özellikleri ile konfigürasyon dosyaları hazırlanarak 18 molekül için de AutoDock Vina programı ile doking gerçekleştirilmiştir. Sonuç ve Tartışma: Karbamazepin molekülü, IL-17 ile en iyi bağlanma afinitesini ve bağlanma profilini göstermiştir. Ayrıca minosiklin, sülfasalazin ve talidomidin moleküllerinin de aktif bölgede sıkıca paketlendiği ortaya çıkmıştır. Bu moleküllerin AS hastalığının tedavisi için bir öncü molekül olabileceği gösterilmiştir.

Anahtar Kelimeler:

Ankilozan Spondilit, IL-17, ilaç yeniden konumlandırma, kör kenetlenme, moleküler kenetlenme

DRUG REPOSITIONING APPROACH FOR THE TREATMENT OF ANKYLOSING SPONDYLITIS

Objective: In this study, it was aimed to determine an FDA-approved molecule that inhibits the IL-17 receptor, which is an important target for the prevention of inflammation in Ankylosing Spondylitis (AS), using the drug repositioning approach.Material and Method: Using the Drug-Gene Interaction database, 18 molecules specific to the active HLA-B gene were identified in AS. Then, the 3D structure of IL-17 was obtained from the RSCB database. I) Blind docking II) Computed Atlas of Surface Topography of Proteins web tool was used to determine the binding package. The interaction between the known inhibitor of IL-17, rhodomyrtone, and IL-17, was determined by molecular docking using grid boxes around the determined binding packages. Accordingly, configuration files were prepared with the selected grid box features, and docking was performed for 18 molecules with the AutoDock Vina program.Result and Discussion: The carbamazepine molecule shows the best binding affinity and binding profile with IL-17. It was also revealed that minocycline, sulfasalazine, and thalidomide are tightly packed in the active site. It has been demonstrated that these molecules may be lead molecules for the treatment of AS disease.

Keywords:

Ankylosing Spondylitis, blind docking, drug repositioning, IL-17, molecular docking,

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