Pan‐PPAR Agonists Based on the Resveratrol Scaffold: Biological Evaluation and Docking Studies

Li, Wei; He, Xinhua; Jia, Haoyan; Zhong, Benhe

doi:10.1002/cmdc.201000360

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…In fact, residues Leu255, Trp264, Val281 and Leu353, that form this pocket and that are involved in the interaction with the aliphatic chain, could be examples of “activity cliff hot spots” 16. This result confirms that the aliphatic chain helps compound 49 to occupy the three pockets of the Y‐shaped binding site, as proposed before 42. This small structural difference is responsible for the activity cliff between compounds 49 76 directly affecting the IC 50 against PPARδ of 49 (223 nM) compared with those of compounds 48 and 76 (2568 nM and 4430 nM, respectively).…”

Section: Resultssupporting

confidence: 79%

“…In fact, the pair 49_76 represents an activity cliff where the only structural difference is the aliphatic chain in 49 . It is thought that the aliphatic chain helps the agonist to interact with the three arms of the Y‐shaped ligand binding site of PPARs 42. The importance of this aliphatic chain has been reported previously and it has been proposed as a pharmacophoric feature for pan PPAR agonists 43…”

Section: Resultsmentioning

confidence: 87%

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Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps

Méndez‐Lucio

Pérez‐Villanueva²,

Castillo

et al. 2012

Molecular Informatics

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Structure-activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay. To illustrate this concept, we discuss a case study where Structure-Activity Similarity maps were used to systematically identify and analyze activity cliff generators present in a dataset of 168 compounds tested against three peroxisome-proliferator-activated receptor (PPAR) subtypes. Single-target and dual-target activity cliff generators for PPARα and δ were identified. In addition, docking calculations of compounds that were classified as cliff generators helped to suggest a hot spot in the target protein responsible of activity cliffs and to analyze its implication in ligand-enzyme interaction.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 87%

Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps

Méndez‐Lucio

Pérez‐Villanueva²,

Castillo

et al. 2012

Molecular Informatics

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“…Moreover, ZBH activates PPARα 21 fold more potently than bezafibrate, and its powerful PPARα activation was further manifested on regulating expression of PPARα target genes in vivo. Molecular docking studies revealed that ZBH could interact with the key amino acid residues (Ser280, Tyr464, Tyr314) in the LBD essential for activation of PPARα and may bind to the receptor in a different mode from that of fenofibric acid (the active form of fenofibrate) and bezafibrate [28]. The two phenyl rings of fenofibric acid were docked into the hydrophobic pocket (also known as “benzophenone” pocket) formed by the helices 3, 6, and 10 adjacent to the AF-2 helix.…”

Section: Discussionmentioning

confidence: 99%

Novel PPAR Pan Agonist, ZBH Ameliorates Hyperlipidemia and Insulin Resistance in High Fat Diet Induced Hyperlipidemic Hamster

Chen¹,

Fan²,

Xie³

et al. 2014

PLoS ONE

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Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC50, 1.75 µM) activate PPARα 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC50, 37.37 µM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5-week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARα target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARα, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia.

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“…Recent study also indicated a role of resveratrol in PF, but the underlying mechanism remains unknown. The effect of resveratrol involves several aspects, including antioxidant effect, cyclooxygenase (COX) inhibition, peroxisome proliferator-activated receptor (PPAR) activation, endothelial nitric oxide synthase (eNOS) induction, silent mating type information regulation 2 homolog 1 (SIRT1) activation, etc (Csiszar, 2011;Lagouge et al, 2006;Li et al, 2010). The expansive effect of resveratrol makes it not to only play a protective role in cardiovascular disease, research during past decades have revealed that resveratrol plays an important role in cancer, diabetes, connective tissue disease, etc (Aggarwal et al, 2004;Szkudelska and Szkudelski, 2010;Elmali et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol inhibits rat pulmonary fibroblast proliferation through modulation of TLR4/NF-B pathway

Li¹

2013

Afr. J. Pharm. Pharmacol.

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Resveratrol shows a powerful therapeutic effect in several cardiovascular diseases and cancer. Recent studies suggest a protective role of resveratrol in pulmonary fibrosis, but the underlying mechanism remains unknown. The aim of the present study is to investigate the anti-inflammatory effect of resveratrol on pulmonary fibrosis and reveal the role of toll like receptor 4 (TLR4) signaling pathway during the process. Pulmonary fibrosis (PF) model in rats was induced by endotracheal perfusion of bleomycin (BLM). Resveratrol treatment was given for three weeks. Blood samples and lung tissues were collected for further investigation. Results showed that the level of interleukin(IL)-1 and IL-6 in blood and lung tissue were both elevated in PF rats when compared with control rats (P<0.05). Resveratrol treatment significantly decreased IL-1 and IL-6 level (P<0.05). Real-time polymerase chain reaction (PCR) and western blot both showed that TLR4 expression in lung tissue from PF rats was upregulated while resveratrol treatment significantly decreased TLR4 expression (P<0.05). Furthermore, primary rat pulmonary fibroblast was cultured. Lipopolysaccharide (LPS) induced cellular proliferation and increased TLR4 and NF-κB expression while NF-κB inhibitor BAY 11-7085 abolished the cell proliferation induced by LPS. Increased TLR4 and NF-κB expression induced by LPS incubation were both diminished by resveratrol (P<0.05). Cellular proliferation was also inhibited by resveratrol treatment. In conclusion, the anti-inflammatory effect of resveratrol may contribute its role in antiproliferation of pulmonary fibroblast and PF therapy. TLR4/NF-κB signaling pathway is also involved in the process.

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Pan‐PPAR Agonists Based on the Resveratrol Scaffold: Biological Evaluation and Docking Studies

Cited by 16 publications

References 31 publications

Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps

Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps

Novel PPAR Pan Agonist, ZBH Ameliorates Hyperlipidemia and Insulin Resistance in High Fat Diet Induced Hyperlipidemic Hamster

Resveratrol inhibits rat pulmonary fibroblast proliferation through modulation of TLR4/NF-B pathway

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