Midkine inhibitors: application of a simple assay procedure to screening of inhibitory compounds.
Midkine inhibitors: application of a simple assay procedure to screening of inhibitory compounds.
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DOI：
10.1186/1755-7682-3-12
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发表时间：
2010-06-21
期刊：
影响因子：
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通讯作者：
Muramatsu T
中科院分区：
文献类型：
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作者：
Matsui T;Ichihara-Tanaka K;Lan C;Muramatsu H;Kondou T;Hirose C;Sakuma S;Muramatsu T
中期因子是一种与肝素结合的细胞因子，与多种疾病的病因有关。因此，中期因子抑制剂有望对许多疾病的治疗有所帮助。我们开发了一种基于成骨细胞中中期因子依赖的迁移来检测中期因子活性的简单方法。中期因子抑制剂被搜索为抑制这种中期因子活性的材料。为了开发抑制中期因子活性的多肽，我们构建了中期因子C端一半与α4β1-整合素相互作用的模型。借助于Presto-X2程序进行电子筛选，寻找有望与中期因子高亲和力结合的低分子化合物。在中期因子和整合素的可能结合部位的多肽中，来源于β1-整合素的多肽和中期因子C末端的第一个β片断对中期因子的活性有显著的抑制作用。电子筛选发现的两个小分子化合物对靶细胞无毒性，但对中期因子活性有抑制作用。它们是三氟化合物：一个(PubChem 4603792)是2-(2，6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine，，另一个具有相关结构。该检测方法有助于中期因子抑制剂的筛选。本文所述的所有试剂可能成为开发临床有效的中期因子抑制剂的母体材料。
Midkine is a heparin-binding cytokine and is involved in etiology of various diseases. Thus, midkine inhibitors are expected to be helpful in treatment of many diseases. We developed a simple assay for midkine activity based on midkine-dependent migration of osteblastic cells. Midkine inhibitors were searched as materials that inhibit this midkine activity. To develop peptides that inhibit midkine activity, we constructed models in which C-terminal half of midkine interacted with α4β1-integrin. Low molecular weight compounds which are expected to bind to midkine with high affinity were searched by in silico screening with the aid of Presto-X2 program. Among peptides in putative binding sites of midkine and the integrin, a peptide derived from β1-integrin and that derived from the first β sheet of the C-terminal half of midkine significantly inhibited midkine activity. Two low molecular weight compounds found by in silico screening exhibited no toxicity to target cells, but inhibited midkine activity. They are trifluoro compounds: one (PubChem 4603792) is 2-(2,6-dimethylpiperidin-1-yl)-4-thiophen-2-yl-6-(trifluoromethy)pyrimidine, and the other has a related structure. The assay procedure is helpful in screening midkine inhibitors. All reagents described here might become mother material to develop clinically effective midkine inhibitors.