Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Scientific Reports
ISSN
2045-2322
e-ISSN
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Volume of the periodical
7
Issue of the periodical within the volume
October
Country of publishing house
GB - UNITED KINGDOM
Number of pages
10
Pages from-to
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UT code for WoS article
000413357100001
EID of the result in the Scopus database
2-s2.0-85031895411