Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F17%3A10368802" target="_blank" >RIV/00216208:11160/17:10368802 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.nature.com/articles/s41598-017-12628-5" target="_blank" >http://www.nature.com/articles/s41598-017-12628-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-017-12628-5" target="_blank" >10.1038/s41598-017-12628-5</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation

Popis výsledku v původním jazyce

The nuclear receptors peroxisome proliferator-activated receptor gamma (PPAR gamma) and its hetero-dimerization partner retinoid X receptor alpha (RXR alpha) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPAR gamma to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPAR gamma and RXR alpha. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPAR gamma and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPAR gamma agonist in vitro with the purified PPAR gamma ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPAR gamma ligand binding domain than magnolol (K-i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPAR gamma-dependent luciferase gene both compounds were equally effective. This is likely due to the PPAR gamma specificity of the newly designed magnolol dimer and lack of RXRa-driven transactivation activity by this dimeric compound.

Název v anglickém jazyce

Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation

Popis výsledku anglicky

The nuclear receptors peroxisome proliferator-activated receptor gamma (PPAR gamma) and its hetero-dimerization partner retinoid X receptor alpha (RXR alpha) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPAR gamma to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPAR gamma and RXR alpha. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPAR gamma and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPAR gamma agonist in vitro with the purified PPAR gamma ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPAR gamma ligand binding domain than magnolol (K-i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPAR gamma-dependent luciferase gene both compounds were equally effective. This is likely due to the PPAR gamma specificity of the newly designed magnolol dimer and lack of RXRa-driven transactivation activity by this dimeric compound.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

—

Svazek periodika

7

Číslo periodika v rámci svazku

October

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

—

Kód UT WoS článku

000413357100001

EID výsledku v databázi Scopus

2-s2.0-85031895411