Abstract

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49∼94.1 nM against AT1 and EC50s of 20∼3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Highlights

  • Type 2 diabetes mellitus (T2DM) was thought to result from the combination of genetic factor, such as lifestyle changing, population aging, exercise reducing [1, 2]

  • For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work

  • Telmisartan matched better with the receptor surface compared with compound 8, illustrating the higher angiotensin II type 1 (AT1) antagonistic activity than 8

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Summary

Introduction

Type 2 diabetes mellitus (T2DM) was thought to result from the combination of genetic factor, such as lifestyle changing, population aging, exercise reducing [1, 2]. It is predicted that the number of people with this disorder will be increasing without highly efficient therapy [3, 4]. Diabetes mellitus was thought to exhibit some relationship with hypertension. The incidence of hypertension occurring to patients with diabetes mellitus is almost twice higher than those with no diabetes mellitus. The greater mortality of patients in diabetes mellitus right attributed to cardiovascular diseases, among which hypertension takes up to high proportion of 75% [5]. Developing novel and potent agents to concurrently treat hyperglycemia and hypertension with high occurrence allows of no delay

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