Synthesis, molecular docking, dynamic simulation and pharmacological characterization of potent multifunctional agent (dual GPR40-PPARγ agonist) for the treatment of experimental type 2 diabetes.

European Journal of Pharmacology
Sergio Hidalgo-FigueroaGabriel Navarrete-Vazquez

Abstract

The current manuscript describes two molecules that were designed against PPARγ and GPR40 receptors. The preparation of the compounds was carried out following a synthetic route of multiple steps. Then, the mRNA expression levels of PPARγ, GLUT4, and GPR40 induced by compounds were measured and quantified in adipocyte and β-pancreatic cell cultures. The synthesized compound 1 caused an increase in the 4-fold expression of mRNA of PPARγ regarding the control and had a similar behavior to the pioglitazone, while compound 2 only increased 2-fold the expression. Also, the compound 1 increased to 7-fold the GLUT4 expression levels, respect to the control and twice against the pioglitazone. On the other hand, the 1 increase 3-fold GPR40 expression, and compound 2 had a minor activity. Besides, 1 and 2 showed a moderated increase on insulin secretion and calcium mobilization versus the glibenclamide. Based on the molecular docking studies, the first compound had a similar conformation to co-crystal ligands into the binding site of both receptors. The poses were docked keeping the most important interactions and maintaining the interaction along the Molecular Dynamics simulation (20 ns). Finally, compound (1) showed an antihyperglycemi...Continue Reading

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