Sumra Dilshad, Shabnam, Arif Ali, Shama Firdaus, Musheer Ahmad, Aiman Ahmad
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The fluorescence titration studies showed moderate binding interaction of <b>1</b> with HuL with Ka of 6.3x10<sup>5</sup> M<sup>-1</sup> at pH-2, 25 °C due to its interaction withAsp53, Tyr63, Val110, and Ala111 as shown by docking and simulation studies. <b>1</b>suppresses the HuL fibrillation in a concentration-dependent manner, as demonstrated by ThT assay. At 200 µM concentration, it leads to the formation of smaller species of the protein in comparison to the control sample, as suggested by Light Scattering studies. The species formed are less hydrophobic and retain their native α-helix structure compared to the control samples, which are hydrophobic and form β-sheet rich amyloids as shown by ANS hydrophobicity assay and CD spectroscopy, respectively. Furthermore, morphological analysis of the species by AFM has demonstrated that, unlike mature amyloid fibrils in the control sample, HuL forms small-size aggregates in the presence of <b>1</b> under similar fibrillation conditions. It can be concluded that <b>1</b> effectively suppresses HuL fibrillation due to moderate binding to the protein.Communicated by Ramaswamy H. 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引用次数: 0
摘要
在这项工作中,成功合成了一种新的铜(II)基配合物作为化疗药物,其配体为[Cu(DCA)4(H2O)2]⋅4H2O⋅4MeOH(DCA = 3,4-二甲氧基肉桂酸),即利用 DCA 作为配体来抑制人类溶菌酶的纤维化。通过单晶 X 射线衍射 (SC-XRD)、光谱(紫外可见光和傅立叶变换红外光谱)技术、PXRD 和 TGA 分析,对 1 进行了全面的表征。其晶体结构显示出围绕中心铜金属离子的桨轮网络。铜(II)金属离子呈扭曲的方形金字塔构型。荧光滴定研究表明,在 pH 值为 2、温度为 25 ℃ 时,1 与 HuL 的结合力中等,其 Ka 值为 6.3x105 M-1,这是由于对接和模拟研究表明 1 与 Asp53、Tyr63、Val110 和 Ala111 发生了相互作用。ThT 试验表明,1 能以浓度依赖性方式抑制 HuL 纤维化。光散射研究表明,在 200 µM 浓度下,与对照样品相比,它能导致形成更小的蛋白质种类。ANS 疏水性检测法和 CD 光谱法分别显示,与对照样品相比,所形成的物种疏水性较低,并保留了其原生的 α-helix 结构;与对照样品相比,所形成的物种疏水性较高,并形成了富含 β-sheet 的淀粉样。此外,用原子力显微镜对这些物种进行的形态分析表明,与对照样本中成熟的淀粉样纤维不同,在类似的纤化条件下,HuL 在 1 的存在下会形成小尺寸的聚集体。由此可以得出结论,由于 1 与蛋白质的结合适度,它能有效抑制 HuL 的纤维化。
Suppression of human lysozyme aggregation by a novel copper-based complex of 3,4-dimethoxycinnamic acid.
In this work, a new Cu(II)-based complex as a chemotherapeutic drug agent, formulated as[Cu(DCA)4(H2O)2]⋅4H2O⋅4MeOH, (DCA = 3,4-dimethoxycinnamic acid), namely 1 was successfully synthesized utilizing DCA as a ligand to arrest fibrillation in Human lysozyme. The 1 was thoroughly characterized by single crystal X-ray diffraction (SC-XRD), spectroscopic (UV-Vis and FTIR) techniques, PXRD, and TGA analysis. Its crystal structure reveals a paddle wheel network around central copper metal ions. The Cu(II) metal ions exhibit a distorted square pyramidal configuration. The fluorescence titration studies showed moderate binding interaction of 1 with HuL with Ka of 6.3x105 M-1 at pH-2, 25 °C due to its interaction withAsp53, Tyr63, Val110, and Ala111 as shown by docking and simulation studies. 1suppresses the HuL fibrillation in a concentration-dependent manner, as demonstrated by ThT assay. At 200 µM concentration, it leads to the formation of smaller species of the protein in comparison to the control sample, as suggested by Light Scattering studies. The species formed are less hydrophobic and retain their native α-helix structure compared to the control samples, which are hydrophobic and form β-sheet rich amyloids as shown by ANS hydrophobicity assay and CD spectroscopy, respectively. Furthermore, morphological analysis of the species by AFM has demonstrated that, unlike mature amyloid fibrils in the control sample, HuL forms small-size aggregates in the presence of 1 under similar fibrillation conditions. It can be concluded that 1 effectively suppresses HuL fibrillation due to moderate binding to the protein.Communicated by Ramaswamy H. Sarma.
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.