Linked magnolol dimer as a selective PPARγ agonist - Structure-based rational design, synthesis, and bioactivity evaluation.
Linked magnolol dimer as a selective PPARγ agonist - Structure-based rational design, synthesis, and bioactivity evaluation.
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DOI：
10.1038/s41598-017-12628-5
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发表时间：
2017-10-20
影响因子：
4.6
通讯作者：
Dirsch VM
中科院分区：
文献类型：
--
作者：
Dreier D;Latkolik S;Rycek L;Schnürch M;Dymáková A;Atanasov AG;Ladurner A;Heiss EH;Stuppner H;Schuster D;Mihovilovic MD;Dirsch VM
核受体过氧化物酶体增殖体激活受体γ (PPARγ)及其异二聚化伙伴类视黄醇X受体α (RXRα)被认为是治疗代谢综合征和2型糖尿病等疾病的药物靶点。人们一直在努力开发新的PPARγ激动剂，以获得比目前使用的药物更有利的配体。厚朴酚以前被描述为PPARγ和RXRα的双重激动剂。在这里，我们展示了PPARγ配体结合域内基于结构的连接厚朴酚二聚体的合理设计及其合成。此外，我们在体外与纯化的PPARγ配体结合域（LBD）和HEK293细胞核受体转激活模型中评估了其作为PPARγ激动剂的结合特性和功能。我们发现合成的厚朴酚二聚体与纯化的PPARγ配体结合域的亲和力比厚朴酚高得多（K i值分别为5.03和64.42 nM）。就其反激活ppar γ依赖性荧光素酶基因的效力而言，两种化合物的效果相同。这可能是由于新设计的厚朴酚二聚体的PPARγ特异性和缺乏rxr α驱动的二聚体化合物的转激活活性。
The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) 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 PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ 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 PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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Stuppner H
影响因子：
2.7
作者：
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通讯作者：
Mihovilovic, Marko D.