Molecular Modeling Study of PPARr Agonists: Dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and Rosiglitazone as Antidiabetic Drugs
Molecular Modeling Study of PPARr Agonists: Dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and Rosiglitazone as Antidiabetic Drugs
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PPARr 激动剂：脱氢二异丁香酚、Macelignan、吡格列酮、奈格列酮和罗格列酮作为抗糖尿病药物的分子模型研究
DOI：
10.5539/ijc.v6n2p48
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
J. Levita
中科院分区：
文献类型：
--
作者：
N. M. Saptarini;F. A. Saputri;J. Levita
过氧化物酶体增殖体激活受体（PPARs）是核受体家族中配体激活的转录因子。本研究的目的是分析PPARr激动剂的分子方面，用于设计新的抗糖尿病药物。分析方法是比较PPARr配体结合域内配体的相互作用。这一分析表明，大多数已知的PPARr激动剂通过氢键与Tyr473相互作用。吡格列酮与His323和Tyr473形成3个氢键。奈托列酮与Ser289、His323、His449和Tyr473有4个氢键。罗格列酮与Ser289、His323、His449和Tyr473有5个氢键。AZ72是PPARr和r的激动剂，与Ser289、His323、His449和Tyr473有5个氢键。采用AutoDock Vina软件对吡格列酮和罗格列酮进行再对接，建立分子模型。对接发现，吡格列酮（Ki 0.22 uM）和罗格列酮（Ki 0.70 uM）均占据了它们的原位点，并与Tyr473相互作用。通过对脱氢双异丁香酚与马塞利木聚糖的对接模拟，可视化其与PPARr的相互作用。这两种化合物是在肉豆蔻的种子（Myristica fragrans Hout）中发现的，已被证明在体外具有抗糖尿病活性。由此可见，为了与Tyr473相互作用，PPARr激动剂必须具有氢键供体和受体基团。Tyr473可能是PPARr配体结合域与其激动剂相互作用的关键位点。
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated trasncription factors belonging to the nuclear receptor family. The objective of this study is to analyze the molecular aspects of PPARr agonists which used to design of new antidiabetic drugs. The analysis method was comparing the interactions of ligands in the ligand binding domain of the PPARr. This analysis showed that most known agonists of PPARr interacted via hydrogen bond with Tyr473. Pioglitazone showed three hydrogen bonds with His323 and Tyr473. Netoglitazone showed four hydrogen bonds with Ser289, His323, His449, and Tyr473. Rosiglitazone showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. AZ72, an agonist of PPARr and r showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. Molecular modeling was performed by redocking pioglitazone and rosiglitazone using AutoDock Vina. Docking showed that both pioglitazone (Ki 0.22 uM) and rosiglitazone (Ki 0.70 uM) occupied their origin sites and interacted with Tyr473. Docking simulation was also performed between dehydro-di-isoeugenol and macelignan to visualize the interaction with PPARr. These two compounds are found in nutmeg’s seed (Myristica fragrans Hout) that have been proven had antidiabetic activity in vitro. It can be concluded that agonists of PPARr should have hydrogen bond donor and acceptor groups for interacting with Tyr473. Tyr473 might be a critical site of interaction between the PPARr ligand binding domain and its agonists.