Mission 2: Search for selective modulators PPARγ

Mission 2: Search for selective modulators PPARγ

MISSION PLAN: Filip Cernatič, dr. Črtomir Podlipnik
Target number: 4
Target identifiers: 22-25
Number of compounds: 10.000.000
Total dockings: 40.000.000
Mission duration: 07.05.2020 – 
Results: in processing


PPARγ is a nuclear receptor that plays a central role in promoting adipocyte growth and differentiation and regulating blood glucose and triglyceride levels. PPARγ exists in two isoforms, PPARγ1 and PPARγ2, of which PPARγ1 is ubiquitous and PPARγ2 is expressed predominantly in adipose tissue. Under normal physiological conditions, PPARγ is the target of a number of post-translational modifications that regulate the transcriptional activity of this receptor. Posttranslational modification of PPARγ by cyclin-dependent kinase 5 (CDK5) leads to suppression of specific genes that increase insulin sensitivity. In obese individuals, proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, invade adipose tissue. Such cytokines accelerate the cleavage of the p35 protein, the CDK5 binding partner, into a more stable and biologically active p25 subunit, which increases CDK5 activity, leading to an excessive extent of PPARγ phosphorylation at the Ser245 site (Ser273 in PPARγ2). The end result of the described course of events is the insulin resistance of the individual – a condition that significantly increases the likelihood of developing type 2 diabetes and cardiovascular disease. Inhibition of PPARγ phosphorylation by CDK5, by binding the ligand to the active site of PPARγ, restores the basal level of transcription and again increases insulin sensitivity [1,2].

In previous decades, several groups of active substances have been developed and approved for the treatment of obesity-related diseases, the most important of which is probably the group of thiazolodindiones (TZDs), full of PPARγ agonists. Due to many side effects of TZD drugs, such as weight gain, excessive water retention, bone loss and anemia, attention has been shifted to the development of selective PPARγ modulators (SPPARMs) in the development of such active substances. , which express a smaller extent of harmful side effects, but still retain strong antidiabetic properties [1,2,3].


[1] Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466(7305):451‐456. doi:10.1038/nature09291

[2] Zieleniak, A., Wójcik, M. & Woźniak, L.A. Structure and physiological functions of the human peroxisome proliferator-activated receptor γ. Arch. Immunol. Ther. Exp. 56, 331 (2008). https://doi.org/10.1007/s00005-008-0037-y

[3] Zhang F, Lavan BE, Gregoire FM. Selective Modulators of PPAR-gamma Activity: Molecular Aspects Related to Obesity and Side-Effects. PPAR Res. 2007;2007:32696. doi:10.1155/2007/3269