Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists

Furukawa, Akihiro; Arita, Tsuyoshi; Fukuzaki, Takehiro; Satoh, Susumu; Mori, Makoto; Honda, Takeshi; Matsui, Yumi; Wakabayashi, Kenji; Hayashi, Shigeru; Araki, Koji; Ohsumi, Jun

doi:10.1016/j.bmcl.2011.12.066

Cited by 15 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple cercosporamides have been found to have partial agonist activity with PPAR γ . Several crystal structures for cercosporamide derivatives bound to PPAR γ exist including Cerco-A and Compounds 23, 17, 21, and 15 [ 54 – 57 ]. The cercosporamides for which there are crystal structures available show less chemical diversity than those of the other classes described in this review.…”

Section: (−)-Cerocosporamidesmentioning

confidence: 99%

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

2015

View full text Add to dashboard Cite

PPARγ (peroxisome proliferator activated receptor γ) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARγ include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARγ have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists.

show abstract

Section: (−)-Cerocosporamidesmentioning

confidence: 99%

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

2015

View full text Add to dashboard Cite

show abstract

“…Because several amino acids were found to be involved in the interactions with hPPARγ ligands (modulators), the set of interacting residues should be ligand-dependent. As an example, in 3V9V.pdb, a derivative of cercosporamide, 33 which acts as a partial agonist, was cocrystalized. This ligand provides several interactions with multiple residues of the protein, including Arg280 (polar contacts) 24 and Ile262, Ile341, Ser342, Met348, Ile281, Leu353, Met343, Leu330, Tyr327, Met364, Lys367, His449, Ser289, Cys285, Arg288, Gly284, and Phe287 (nonpolar contacts).…”

Section: Resultsmentioning

confidence: 99%

In silico approach for the discovery of new PPARγ modulators among plant-derived polyphenols

Encinar¹,

Fernández‐Ballester²,

Galiano³

et al. 2015

DDDT

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-characterized member of the PPAR family that is predominantly expressed in adipose tissue and plays a significant role in lipid metabolism, adipogenesis, glucose homeostasis, and insulin sensitization. Full agonists of synthetic thiazolidinediones (TZDs) have been therapeutically used in clinical practice to treat type 2 diabetes for many years. Although it can effectively lower blood glucose levels and improve insulin sensitivity, the administration of TZDs has been associated with severe side effects. Based on recent evidence obtained with plant-derived polyphenols, the present in silico study aimed at finding new selective human PPARγ (hPPARγ) modulators that are able to improve glucose homeostasis with reduced side effects compared with TZDs. Docking experiments have been used to select compounds with strong binding affinity (ΔG values ranging from −10.0±0.9 to −11.4±0.9 kcal/mol) by docking against the binding site of several X-ray structures of hPPARγ. These putative modulators present several molecular interactions with the binding site of the protein. Additionally, most of the selected compounds have favorable druggability and good ADMET properties. These results aim to pave the way for further bench-scale analysis for the discovery of new modulators of hPPARγ that do not induce any side effects.

show abstract

“…Several groups have investigated the mechanism of PPARγ partial agonism using small numbers of selected test compounds. ,,− Initial studies have revealed that partial agonists can operate through at least two different structural mechanisms defined by the portions of the binding pockets that they occupy. The first class binds only in the portion of the pocket proximal to the β-sheet (Figure B); the compounds are positioned between the β-sheet and helix 3.…”

Section: Resultsmentioning

confidence: 99%

SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism

et al. 2015

View full text Add to dashboard Cite

Synthetic full agonists of PPARγ have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARγ has been hampered due to severe side effects, partial agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARγ to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 Å resolution demonstrates that interactions with the β-sheet are driven exclusively via hydrophobic interactions mediated through a naphthalene group, an observation that is unique from other partial agonists. Surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (KD = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.

show abstract

Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists

Cited by 15 publications

References 25 publications

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

In silico approach for the discovery of new PPARγ modulators among plant-derived polyphenols

SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism

Contact Info

Product

Resources

About

Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists

Cited by 15 publications

References 25 publications

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

Review of the Structural and Dynamic Mechanisms of PPARγPartial Agonism

In silico approach for the discovery of new PPAR&gamma; modulators among plant-derived polyphenols

SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism

Contact Info

Product

Resources

About

In silico approach for the discovery of new PPARγ modulators among plant-derived polyphenols