SAR and Computer-Aided Drug Design Approaches in the Discovery of Peroxisome Proliferator-Activated Receptor γ Activators: A Perspective

Abstract

Activators of PPARγ, Troglitazone (TGZ), Rosiglitazone (RGZ), and Pioglitazone (PGZ) were introduced for treatment of Type 2 diabetes, but TGZ and RGZ have been withdrawn from the market along with other promising leads due cardiovascular side effects and hepatotoxicity. However, the continuously improving understanding of the structure/function of PPARγand its interactions with potential ligands maintain the importance of PPARγas an antidiabetic target. Extensive structure activity relationship (SAR) studies have thus been performed on a variety of structural scaffolds by various research groups. Computer-aided drug discovery (CADD) approaches have also played a vital role in the search and optimization of potential lead compounds. This paper focuses on these approaches adopted for the discovery of PPARγligands for the treatment of Type 2 diabetes. Key concepts employed during the discovery phase, classification based on agonistic character, applications of various QSAR, pharmacophore mapping, virtual screening, molecular docking, and molecular dynamics studies are highlighted. Molecular level analysis of the dynamic nature of ligand-receptor interaction is presented for the future design of ligands with better potency and safety profiles. Recently identified mechanism of inhibition of phosphorylation of PPARγat SER273 by ligands is reviewed as a new strategy to identify novel drug candidates.

Structural and Dynamical Insight into PPARγ Antagonism: In Silico Study of the Ligand-Receptor Interactions of Non-Covalent Antagonists

“…This further supports our hypothesis that ligand 9l could also be expected to have increased transcriptional activity compared to 9k. It is well known that the conformation of the so called charge-clamp pair [ 10 , 22 ], which consists of the residues Lys301 and Glu471, is critical for the coactivator binding [ 23 , 24 ], in parallel with the important role of Tyr473 for the PPARγ agonistic features [ 5 ]. Thus, our data reveal the main reason of the observed antagonism of the compound 9p: it can be related to the disruption of the binding pockets of both the natural ligand and the coactivator, due to the described above structural perturbation induced by its interactions.…”

“…A lot of data are available about the dynamics of peroxisome proliferator-activated receptor γ (PPARγ) and its agonists, collected by several experimental techniques such as hydrogen deuterium exchange (HDX) mass spectrometry, NMR and fluorescence anisotropy [ 1 , 2 , 3 , 4 , 5 ]. A detailed binding mode of this class of compounds has also been revealed by many X-ray structures deposed in the Protein Data Bank (PDB) [ 6 ].…”

“…The commonly adopted conception about the dynamics of the PPARγ full agonists relies on experimental data and suggests that they stabilize the H12 position, compared to the apo protein form, through interactions with the residue Tyr473 in particular. Other parts of the ligand-binding domain (LBD), such as H11 and H3, are also considered to play a role in the agonistic conformation of the receptor [ 5 ]. However, the observed conformational changes in H12 seem to be much smaller compared to other nuclear receptors, as, for example, it has been demonstrated for the estrogen receptor α (ERα) [ 10 , 11 ] and additionally by employing accelerated molecular dynamics (MD) [ 12 ].…”

Structural Basis for the Enhanced Anti-Diabetic Efficacy of Lobeglitazone on PPARγ

“…In silico drug design approaches are commonly used for the target identification, validation, molecular design, and drug interactions with target proteins 29 . A number of computer-aided drug discovery studies have been also conducted to find new insulin sensitizing molecules targeting PPARγ with reduced toxicity and side effects 30 . In silico studies have been reported using the structure of PPARγ LBD in complex with rosiglitazone, a representative anti-diabetic drug for PPARγ 31 , 32 .…”

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome

“…A promising approach for both studying and treating metabolic syndrome involves the use of a class of drugs called thiazolidinediones [14–17], previously used to treat diabetes. Rosiglitazone (RGZ), the prototypical drug in this class, activates the nuclear peroxisome proliferator-activated receptor γ (PPARγ), a type II nuclear receptor, which in turn alters the expression of numerous genes [18], ultimately resulting in reduced blood concentrations of glucose, fatty acids, and insulin [19].…”