İlaç Yeniden Konumlandırma Yaklaşımı ile Alfa Tübülin Asetilasyonunu Arttırabilecek Bileşiklerin Araştırılması

Abstract

Drug repurposing approach is used to identify new indications of drugs outside the scope of their original indications. This approach has been used to identify effective compounds for neurodegenerative diseases. Axonal transport defects are one of the common molecular findings in neurodegenerative diseases and the transport involves microtubules. α-tubulin, a structural protein of microtubules, are subjected to several post-translational modifications. In model systems of neurodegenerative diseases, reduced α-tubulin acetylation are associated with impaired axonal transport, which could be restored by increasing α-tubulin acetylation via histone deacetylase 6 (HDAC6) inhibition. Therefore, HDAC6 is considered as a potential drug target. In this thesis, among clinically approved compounds, it was aimed to determine a compound capable of increasing α-tubulin acetylation by affecting HDAC6 using drug repurposing approach. The thesis was initiated with 7 FDA-approved compounds and the activity of 3 compounds was investigated in vitro as a result of in silico studies, involving molecular docking, chemoinformatics and comparative structural analysis. Among them, rutin and riboflavin was found to inhibit HDAC6 activity. Compounds were applied to NSC34 cells and subsequent western blot studies showed no alterations in α-tubulin acetylation in riboflavin-treated cells. However, α-tubulin acetylation was significantly increased in 24 hours rutin-treated cells at 100 and 1000 µM concentrations. In conclusion, it has been shown for the first time that the rutin inhibits the activity of the HDAC6 and increases the acetylation of α-tubulin. Further studies will be valuable to determine the impacts of rutin on axonal transport defects.