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

Type 2 diabetes mellitus is described by insulin resistance and high fasting blood glucose. Increased levels of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme result in insulin resistance and metabolic syndrome. Inhibition of 11ß-HSD1 decreases glucose production and increases hepatic insulin sensitivity. Use of selective 11ß-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 11ß-HSD1 inhibitory activity. A dataset of 139 triazoles and tetrazoles having 11ß-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 [Formula: see text] = 0.809 with five components, [Formula: see text] = 0.931, SEE = 0.323 and F-value = 249.126. The CoMSIA model offered better prediction than the CoMFA model with [Formula: see text] = 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 11ß-HSD1 inhibitors. The selectivity aspect of 11ß-HSD1 over 11ß-HSD2 was studied with the help of docking studies.

Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity.

Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.