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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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Related in: MedlinePlus

The docking mode of representative Cpd#1 with the active site of peroxisome proliferator-activated receptor (PPAR)α (A), PPARγ (B), and PPARδ (C).Note: The original ligands AZ242 (left), rosiglitazone (middle), and TIPP204 (right) are colored in purple.
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f3-dddt-8-2255: The docking mode of representative Cpd#1 with the active site of peroxisome proliferator-activated receptor (PPAR)α (A), PPARγ (B), and PPARδ (C).Note: The original ligands AZ242 (left), rosiglitazone (middle), and TIPP204 (right) are colored in purple.

Mentions: The docking mode of the representative Cpd#1 with the active site of PPARα/γ/δ receptors is shown in Figure 3. The carboxyl acidic head of Cpd#1 formed hydrogen bonds with the key residues of PPARα (Ser280, Tyr314, Tyr464, and His440), PPARγ (Ser289, His323, Tyr473, and His449), and PPARδ (His323, His449, and Tyr473) receptors, respectively. The aromatic hydrophobic tail and the linker of Cpd#1 bound to PPARα/γ/δ with similar conformations to the original ligand AZ242, rosiglitazone, and TIPP204, respectively.


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)

The docking mode of representative Cpd#1 with the active site of peroxisome proliferator-activated receptor (PPAR)α (A), PPARγ (B), and PPARδ (C).Note: The original ligands AZ242 (left), rosiglitazone (middle), and TIPP204 (right) are colored in purple.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-8-2255: The docking mode of representative Cpd#1 with the active site of peroxisome proliferator-activated receptor (PPAR)α (A), PPARγ (B), and PPARδ (C).Note: The original ligands AZ242 (left), rosiglitazone (middle), and TIPP204 (right) are colored in purple.
Mentions: The docking mode of the representative Cpd#1 with the active site of PPARα/γ/δ receptors is shown in Figure 3. The carboxyl acidic head of Cpd#1 formed hydrogen bonds with the key residues of PPARα (Ser280, Tyr314, Tyr464, and His440), PPARγ (Ser289, His323, Tyr473, and His449), and PPARδ (His323, His449, and Tyr473) receptors, respectively. The aromatic hydrophobic tail and the linker of Cpd#1 bound to PPARα/γ/δ with similar conformations to the original ligand AZ242, rosiglitazone, and TIPP204, respectively.

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