Groove binding mediated structural modulation and DNA cleavage by quinoline appended chalcone derivative.
Groove binding mediated structural modulation and DNA cleavage by quinoline appended chalcone derivative.
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DOI：
10.1016/j.saa.2015.07.010
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
H. Kumar;Vinod Devaraji;R. Prasath;M. Jadhao;R. Joshi;P. Bhavana;S. Ghosh
中科院分区：
文献类型：
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作者：
H. Kumar;Vinod Devaraji;R. Prasath;M. Jadhao;R. Joshi;P. Bhavana;S. Ghosh
本研究通过紫外可见吸收、稳态荧光光谱、荧光各向异性、圆二色性、螺旋溶解、琼脂糖凝胶电泳、分子对接、诱导拟合对接（IFD）和分子动力学（MD）模拟，详细研究了潜在生物活性喹啉附加查尔酮衍生物(E)-3-（蒽-10-基）-1-（6,8-二溴-2-甲基喹啉-3-基）prop-2-en-1-one （ADMQ）与小牛胸腺DNA （ctDNA）的DNA结合作用及其结果。紫外-可见吸收和荧光研究表明，该分子与核酸发生相当大的相互作用。对照KI猝灭实验表明，在ctDNA存在下，ADMQ分子对离子猝灭剂（I−）的可及性较弱。螺旋熔化温度和圆二色光谱的变化不明显，表明非共价槽结合相互作用。该查尔酮衍生物（各向异性= 0.106）在核酸环境中的适度旋转约束，与著名的小凹槽结合剂Hoechst 33258和插入剂Ethidium Bromide进行比较位移测定，建立了探针分子的小凹槽结合相互作用。分子对接、IFD和MD模拟显示，DNA在螺旋解绕和弯曲方面发生了显著的形态学变化，以适应ADMQ以序列特定的方式呈110°角的新月形。在相互作用过程中，ADMQ使核酸的糖磷酸主链硬化和弯曲，从而使其总长度缩短3.02 Å。质粒pBR 322琼脂糖凝胶电泳实验表明，凹槽结合的ADMQ导致质粒DNA的浓度依赖性切割成其超螺旋和缺口圆形。本文所描述的综合光谱研究为杂环查尔酮衍生物与相关靶核酸的相互作用提供了定量的见解，这可能对未来查尔酮类治疗剂的研究有帮助。
The present study embodies the detail DNA binding interaction of a potential bioactive quinoline appended chalcone derivative (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) with calf thymus DNA (ctDNA) and its consequences by UV–Vis absorption, steady state fluorescence spectroscopy, fluorescence anisotropy, circular dichromism, helix melting, agarose gel electrophoresis, molecular docking, Induced Fit Docking (IFD) and molecular dynamics (MD) simulation. The UV–Vis absorption and fluorescence study reveal that the molecule undergoes considerable interaction with the nucleic acid. The control KI quenching experiment shows the lesser accessibility of ADMQ molecule to the ionic quencher (I−) in presence of ctDNA as compared to the bulk aqueous phase. Insignificant change in helix melting temperature as well as in circular dichromism (CD) spectra points toward non-covalent groove binding interaction. The moderate rotational confinement of this chalcone derivative (anisotropy = 0.106) trapped in the nucleic acid environment, the comparative displacement assay with well-known minor groove binder Hoechst 33258 and intercalator Ethidium Bromide establishes the minor groove binding interactions of the probe molecule. Molecular docking, IFD and MD simulation reveal that the DNA undergoes prominent morphological changes in terms of helix unwinding and bending to accommodate ADMQ in a crescent shape at an angle of 110° in a sequence specific manner. During interaction, ADMQ rigidifies and bends the sugar phosphate backbone of the nucleic acid and thereby shortens its overall length by 3.02 Å. Agarose gel electrophoresis experiment with plasmid pBR 322 reveals that the groove binded ADMQ result in a concentration dependent cleavage of plasmid DNA into its supercoiled and nicked circular form. The consolidated spectroscopic research described herein provides quantitative insight into the interaction of a heterocyclic chalcone derivative with relevant target nucleic acid, which may be useful for the future research on chalcone based therapeutic agents.