Screening potential inhibitors of 11BHSD1 for antidiabetic drug development from TCM (traditional Chinese Medicine) compound library from Taiwan

Abstract

11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD1) enzyme is responsible for catalyst the Cortisone to Cortisol reaction. Some disorders in the metabolic system make the regulation not working, Cortisol is produced continuously. It leads the increasing glucose level in blood and it is one of the reasons causing Type 2 Diabetes. Type 2 diabetes cases increase very fast in recent years affecting to the global health and economic due to the payment for diabetes treatment. Many researches are performed to find out the way to treat the type 2 diabetes. This study was carried out to screening the potential inhibitors from the Traditional Chinese Medicine library at Taiwan to develop the antidiabetic drugs by the ensemble docking method combining with molecular dynamics simulations. From 58,000 compounds, screening the inhibitors was performed by Autodock vina to narrow the objects. Besides that, the 11βHSD1’s structure protein was refined by MD simulations to get the stable structure. Then the screened compounds are docked again to refined protein to get more accuracy result. Finally, after calculating the predicted Ki, the 14 compounds having lowest predicted Ki were chosen to make the pharmacophore and schematic diagrams. All 14 compounds bind at the position ILE121, there are some binding positions such as GLY41, SER43, LYS44, ILE46, THR 64, ALA65, ARG66, MET93, ASN119, HIS 120, ILE 218, ASP219, THR220, and GLU221. They are the coenzyme site on 11βHSD1 protein. So, the inhibitors prevent the interaction of coenzyme and protein leading the inhibition of protein. This study gave an opportunity in the treatment of type 2 diabetes and the other diseases based on the nature compounds. Hopefully, the abundant potential traditional medicine are focused and developed in the future. Key words: 11βHSD1, Type 2 Diabetes, Inhibitor, Traditional Chinese Medicine, Autodock vina, Molecular dynamic simulation.