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Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

Wang XJ, Zhang J, Wang SQ, Xu WR, Cheng XC, Wang RL - Drug Des Devel Ther (2014)

Bottom Line: The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure.The single and selective agonism of PPARγ is the main cause of these side effects.Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.

ABSTRACT
The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.

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Thiazolidinediones and fibrates.
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f1-dddt-8-2255: Thiazolidinediones and fibrates.

Mentions: Peroxisome proliferator-activated receptors (PPARs) are nuclear ligand-activated transcription factors and include three subtypes, namely PPARα, PPARγ, and PPARδ.1–3 The drugs targeting PPARs mainly include: 1) PPARγ agonists4 such as rosiglitazone and pioglitazone, which are used as antidiabetic drugs and also possess anti-inflammatory or antineoplastic activities,5,6 and 2) PPARα agonists such as fenofibrate and bezafibrate, which are used as antilipemic drugs (Figure 1).7,8 Rosiglitazone and pioglitazone have shown side effects in clinical use, such as liver function abnormity, edema, and weight gain.9 Especially in 2007, Nissen and Wolski10 reported the cardiac safety of rosiglitazone, which showed that singly selective agonism of PPARγ not only enhanced insulin sensitivity and the therapeutic effect of insulin metabolism but also caused edema, weight gain, and the potential risk of heart failure.


Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.

Wang XJ, Zhang J, Wang SQ, Xu WR, Cheng XC, Wang RL - Drug Des Devel Ther (2014)

Thiazolidinediones and fibrates.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232041&req=5

f1-dddt-8-2255: Thiazolidinediones and fibrates.
Mentions: Peroxisome proliferator-activated receptors (PPARs) are nuclear ligand-activated transcription factors and include three subtypes, namely PPARα, PPARγ, and PPARδ.1–3 The drugs targeting PPARs mainly include: 1) PPARγ agonists4 such as rosiglitazone and pioglitazone, which are used as antidiabetic drugs and also possess anti-inflammatory or antineoplastic activities,5,6 and 2) PPARα agonists such as fenofibrate and bezafibrate, which are used as antilipemic drugs (Figure 1).7,8 Rosiglitazone and pioglitazone have shown side effects in clinical use, such as liver function abnormity, edema, and weight gain.9 Especially in 2007, Nissen and Wolski10 reported the cardiac safety of rosiglitazone, which showed that singly selective agonism of PPARγ not only enhanced insulin sensitivity and the therapeutic effect of insulin metabolism but also caused edema, weight gain, and the potential risk of heart failure.

Bottom Line: The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure.The single and selective agonism of PPARγ is the main cause of these side effects.Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.

ABSTRACT
The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.

Show MeSH
Related in: MedlinePlus