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Binding properties of marine bromophenols with human protein tyrosine phosphatase 1B: Molecular docking, surface plasmon resonance and cellular insulin resistance study.
International Journal of Biological Macromolecules ( IF 8.2 ) Pub Date : 2020-06-30 , DOI: 10.1016/j.ijbiomac.2020.06.263
Jiao Luo 1 , Renshuai Zhang 2 , Xuehe Wang 3 , Zhanhui Hou 4 , Shuju Guo 4 , Bo Jiang 4
Affiliation  

Protein tyrosine phosphatase 1B (PTP1B) is a highly validated target for the treatment of type 2 diabetes and obesity. Previous studies have shown that bromophenols from marine red alga Rhodomela confervoides can inhibit PTP1B activity. However, traditional in vitro enzymatic assays may result in false positive activity. Here, we reported a successful application of molecular docking and surface plasmon resonance (SPR) assay for the characterization of small-molecule PTP1B inhibitors with high affinity. First, molecular docking study indicated that six bromophenol compounds preferred to bind PTP1B with open conformation rather than one with closed conformation. Next, SPR study indicated that compound 3 was the most potent and stable PTP1B inhibitor at the nanomolar level. Then Lineweaver–Burk plot data showed that compound 3 was a competitive PTP1B inhibitor. Moreover, compound 3 could improve palmitate-induced insulin resistance in HepG2 cells. Taken together, molecular docking and SPR-based methodology could apply in the development of PTP1B inhibitors with high affinity.



中文翻译:

海洋溴酚与人蛋白质酪氨酸磷酸酶1B的结合特性:分子对接,表面等离振子共振和细胞胰岛素抵抗研究。

蛋白酪氨酸磷酸酶1B(PTP1B)是用于治疗2型糖尿病和肥胖症的高度验证的靶标。先前的研究表明,海洋红藻红景天中的溴酚可以抑制PTP1B活性。但是,传统的体外酶法测定可能会导致假阳性活动。在这里,我们报道了分子对接和表面等离振子共振(SPR)分析在表征高亲和力小分子PTP1B抑制剂方面的成功应用。首先,分子对接研究表明,六种溴酚化合物更喜欢以开放构象结合PTP1B,而不是封闭构象。接下来,SPR研究表明,在纳摩尔水平上,化合物3是最有效,最稳定的PTP1B抑制剂。然后Lineweaver-Burk图数据显示化合物3是竞争性PTP1B抑制剂。而且,化合物3可以改善棕榈酸酯诱导的HepG2细胞中的胰岛素抵抗。两者合计,分子对接和基于SPR的方法可应用于具有高亲和力的PTP1B抑制剂的开发。

更新日期:2020-07-06
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