College of Pharmacy, Department of Medicinal Chemistry, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, UK.
Bioorg Chem. 2024 Jul;148:107414. doi: 10.1016/j.bioorg.2024.107414. Epub 2024 May 8.
Spectroscopic, biochemical, and computational modelling studies have been used to assess the binding capability of a set of minor groove binding (MGB) ligands against the self-complementary DNA sequences 5'-d(CGCACTAGTGCG)-3' and 5'-d(CGCAGTACTGCG)-3'. The ligands were carefully designed to target the DNA response element, 5'-WGWWCW-3', the binding site for several nuclear receptors. Basic 1D H NMR spectra of the DNA samples prepared with three MGB ligands show subtle variations suggestive of how each ligand associates with the double helical structure of both DNA sequences. The variations among the investigated ligands were reflected in the line shape and intensity of 1D H and P-{H} NMR spectra. Rapid visual inspection of these 1D NMR spectra proves to be beneficial in providing valuable insights on MGB binding molecules. The NMR results were consistent with the findings from both UV DNA denaturation and molecular modelling studies. Both the NMR spectroscopic and computational analyses indicate that the investigated ligands bind to the minor grooves as antiparallel side-by-side dimers in a head-to-tail fashion. Moreover, comparisons with results from biochemical studies offered valuable insights into the mechanism of action, and antitumor activity of MGBs in relation to their structures, essential pre-requisites for future optimization of MGBs as therapeutic agents.
光谱学、生物化学和计算建模研究已被用于评估一组小沟结合（MGB）配体与自我互补 DNA 序列 5'-d(CGCACTAGTGCG)-3' 和 5'-d(CGCAGTACTGCG)-3' 的结合能力。这些配体经过精心设计，以靶向 DNA 反应元件 5'-WGWWCW-3'，这是几个核受体的结合位点。用三种 MGB 配体制备的 DNA 样品的基本 1D H NMR 光谱显示出细微的变化，表明每个配体如何与两个 DNA 序列的双螺旋结构结合。研究中配体之间的差异反映在 1D H 和 P-{H}NMR 光谱的线形状和强度上。快速直观地检查这些 1D NMR 光谱有助于提供有关 MGB 结合分子的有价值的见解。NMR 结果与 UV DNA 变性和分子建模研究的结果一致。NMR 光谱和计算分析都表明，所研究的配体以头对头、尾对尾的方式结合到小沟中，形成反平行的侧-侧二聚体。此外，与生化研究结果的比较提供了对作用机制的有价值的见解，以及 MGB 与结构的抗肿瘤活性之间的关系，这是未来作为治疗剂优化 MGB 的必要前提。
