Development of a credible 3D-QSAR CoMSIA model and docking studies for a series of triazoles and tetrazoles containing 11β-HSD1 inhibitors

Abstract

Type 2 diabetes mellitus is described by insulin resistance and high fasting blood glucose. Increased levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme result in insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 decreases glucose production and increases hepatic insulin sensitivity. Use of selective 11β-HSD1 inhibitors could prove to be an effective strategy for the treatment of the disease. It was decided to identify the essential structural features required by any compound to possess 11β-HSD1 inhibitory activity. A dataset of 139 triazoles and tetrazoles having 11β-HSD1 inhibitory activity was used for the development of a 3D-QSAR model. The best comparative molecular field analysis (CoMFA) model was generated with databased alignment, which was further used for comparative molecular similarity indices analysis (CoMSIA). The optimal CoMSIA model showed  = 0.809 with five components, = 0.931, SEE = 0.323 and F-value = 249.126. The CoMSIA model offered better prediction than the CoMFA model with = 0.522 and 0.439, respectively, indicating that the CoMSIA model appeared to be a better one for the prediction of activity for the newly designed 11β-HSD1 inhibitors. The selectivity aspect of 11β-HSD1 over 11β-HSD2 was studied with the help of docking studies.

Keywords:

• 11β-HSD1
• 11β-HSD2
• triazole
• tetrazole
• 3D-QSAR
• docking