"Click" Dendrimers as Anti-inflammatory Agents: With Insights into Their Binding from Molecular Modeling Studies
"Click" Dendrimers as Anti-inflammatory Agents: With Insights into Their Binding from Molecular Modeling Studies
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DOI：
10.1021/mp4000508
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发表时间：
2013-06-01
影响因子：
4.9
通讯作者：
Kakkar, Ashok
中科院分区：
文献类型：
--
作者：
Neibert, Kevin;Gosein, Varin;Kakkar, Ashok
这些研究探索了低代树枝状聚合物在受刺激的小胶质细胞中的抑制作用与树枝状聚合物-酶相互作用之间的关系。低代（DG 0和DG 1）树枝状大分子与乙炔和羟基末端基团进行了测试，其抗炎活性在小胶质细胞刺激脂多糖（LPS），并与那些从建立抗炎剂，布洛芬和塞来昔布的结果进行了比较。我们假设DGO和DG 1树枝状聚合物的羟基末端基团可以与诱导型一氧化氮合酶（iNOS）和环氧合酶-2（考克斯2）酶的活性位点相互作用，这是由于它们的小尺寸和有利的电化学性质。在低代树枝状聚合物存在下，使用生物化学测定法测定iNOS和考克斯-2的酶活性，并且其值与来自计算机分子建模的树枝状聚合物对接确认相关。我们发现，从分子建模研究的结果与体外生物学数据相关性很好，这表明，确实，羟基末端基团的低代树枝状聚合物使多价大分子相互作用，导致抑制iNOS和考克斯-2酶。
These studies explore the relationship between the inhibitory actions of low generation dendrimers in stimulated microglia and dendrimer-enzyme interactions using in silico molecular modeling. Low generation (DG0 and DG1) dendrimers with acetylene and hydroxyl terminal groups were tested for their anti-inflammatory activity in microglia stimulated by lipopolysaccharides (LPS), and the results were compared with those from the established anti-inflammatory agents, ibuprofen and celecoxib. We hypothesized that hydroxyl terminal groups of DGO and DG1 dendrimers could interact with the active sites of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2) enzymes due to their small size and favorable electrochemical properties. The enzymatic activity of iNOS and COX-2 was determined in the presence of low generation dendrimers using biochemical assays and their values related to dendrimer docking confirmations from in silico molecular modeling. We found that results from the molecular modeling studies correlated well with the in vitro biological data, suggesting that, indeed, hydroxyl terminal groups of low generation dendrimers enable multivalent macromolecular interactions, resulting in the inhibition of both iNOS and COX-2 enzymes.