Abstract
As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.
Highlights
Type 2 diabetes are characterized by hyperglycemia, insulin resistance and defects in insulin secretion, the patient with type 2 diabetes often suffer from symptoms of dyslipidemia, hypertension as well as obesity [1]
As important members of nuclear receptor superfamily, Peroxisome proliferatoractivated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms [3], these receptors have been considered as attractive targets for treating type 2 diabetes
1. ligand-binding Domains of the PPAR Receptors Experimental evidences showed that the biological functions of PPAR receptors is regulated by the precise shape of their ligandbinding domain induced by the binding of ligands including a number of coactivators and corepressor proteins
Summary
Type 2 diabetes are characterized by hyperglycemia, insulin resistance and defects in insulin secretion, the patient with type 2 diabetes often suffer from symptoms of dyslipidemia, hypertension as well as obesity [1]. Due to its crucial role in the fatty acid oxidation in the liver cells, PPARa can increase the energy consumption so as to achieve the controlling of energy metabolism and body weight [9] This PPAR receptor can be used as an anti-obesity target, against which a number of clinical drugs (i.e., beclofibrate, bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil) have been approved by US Food and Drug Administration (FDA) to treat the dyslipidemia. PPARc is expressed in adipose tissue, macrophages and vascular smooth muscles at high levels The activation of this PPAR receptor can increase the differentiation of the fat cells, improve the storage of fatty acids and enhance insulin sensitivity in the adipose tissue, skeletal muscle and liver [6,14]. We employed molecular modeling technologies with a core hopping approach to screen the fragment database, with an aim of searching for novel PPAR panagonists to treat type 2 diabetes
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