Structure-based Nuclear Receptors Modeling for Inflammation Research

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARs exist as three different isoforms: α, δ/β, and γ. PPAR activators have been shown to exert anti-inflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases, and acute-phase proteins. Creative Biolabs has established the most exquisite service platform to provide one-stop nuclear receptor modeling services to support and advance your projects.

PPARs in Inflammation

Inflammatory conditions are mainly characterized by activation of macrophages and monocytes at the injury site which subsequently increases the release of proinflammatory mediators like TNF-α, IL-6, and IL-1β, then they stimulate the production of COX products. PPARα and fenofibrate reduce pain and inflammation and further inhibits the release of several pro-inflammatory and pro-angiogenic enzymes and mediators. More recently, PPARγ has been shown to play a fundamentally important role in the immune response through its ability to inhibit the expression of inflammatory cytokines and to direct the differentiation of immune cells toward anti-inflammatory phenotypes. A feature of PPARγ is the structural diversity of its ligands, which encompass endogenous metabolites, dietary compounds, and synthetic drugs. In addition, the natural PPARγ agonists found in foods may be beneficial to human health by acting as anti-inflammatory molecules. PPARγ is, therefore, an interesting target of the pharmaceutical industry.

Molecular modeling studies on PPAR ligands were mainly focused on PPARγ agonists. 3D-QSAR studies on thiazolidine-2,4-diones and N -(2-benzoylphenyl)-l-tyrosine derivatives as PPARγ agonists have been performed to design new antidiabetic drugs. The 3D-QSAR analysis suggested that hydrogen bonds between one carbonyl oxygen atom of the ligand and PPARγ, as well as other hydrophilic interactions, are necessary for activity. A pharmacophore of PPARγ agonists includes a polar head, a hydrophobic tail, and a linker. And potent PPARγ agonists adopt a tail-down configuration like rosiglitazone. Furthermore, agonists for the γ subtype possess a hydrophobic tail containing an alkyl group and an aromatic ring.

Fig.1 Diagram of QSAR based on the core structure of PPARγ agonists.

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PPARγ activation promotes the expression of anti-inflammatory mediators, including IL-10 and liver X receptors, and contributes to the phenotype of alternatively activated macrophages that exert suppressive effects on inflammation. Studies of the intersection of nuclear receptors and inflammation have revealed mechanisms of positive and negative transcriptional control that may provide new targets for pharmacological intervention in chronic diseases such as atherosclerosis. Structure-based modeling remains one of the most important techniques for obtaining a rational 3D structural model to use in ligand design. We can offer a variety of nuclear receptors modeling services to meet specific customer requirements.

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