a Faculty of Sciences, Department of Biology , Islamic Azad University, Mashhad Branch , Mashhad , Iran.
b Department of Biology, Science and Research Branch , Islamic Azad University , Tehran , Iran.
J Biomol Struct Dyn. 2019 Feb;37(2):359-371. doi: 10.1080/07391102.2018.1427629. Epub 2018 Feb 6.
DNA is the primary target of many anticancer drugs involved in important intercellular processes, especially in transcriptional regulation, and histone is known to inhibit gene expression. Small molecules can bind to histone-DNA and impair the cell division, growth, inhibition, and apoptosis in cancer cells. In this research, the interaction of a histone H1-calf thymus DNA (ct DNA) complex and propyl acridone (PA) was investigated in Tris-HCl buffer, pH 6.8, using multi-spectroscopic, viscosity, and molecular modeling techniques. The Stern Volmer plot of the (H1-ct DNA) PA complex demonstrated two sets of binding sites with various binding affinities at three different temperatures. Thermodynamic parameters (ΔH° < 0 and ΔS° < 0) indicated that hydrogen bonds and van der Waals forces played the main roles in the binding of the drug to H1-ct DNA. The interaction between PA and ct DNA as well as (H1-ct-DNA) in the presence of acridine orange and ethidium bromide showed two different interaction behaviors in ternary systems. According to results from UV absorption spectroscopy and melting temperature (Tm) measurements, the binding mode of PA with ct DNA and the (H1-ct DNA) complex was indicative of an intercalative binding for the binary system and of both intercalative with groove binding with molecular fraction for the ternary system. Furthermore, the PA-induced detectable changes in the circular dichroism spectrum of ct DNA as well as changes in its viscosity. All of the experimental results proved that the intercalative binding between PA and ct DNA as well as the (H1-ct DNA) complex as binary and ternary systems must be predominant. The results obtained from experimental data were in good agreement with molecular modeling with regard to the determination of the binding site of PA to ct DNA in the absence and presence of histone H1.
DNA 是许多参与重要细胞内过程的抗癌药物的主要靶点，特别是在转录调控中，组蛋白已知会抑制基因表达。小分子可以与组蛋白-DNA 结合，从而损害癌细胞的分裂、生长、抑制和凋亡。在这项研究中，在 Tris-HCl 缓冲液中，使用多光谱、粘度和分子建模技术研究了组蛋白 H1-小牛胸腺 DNA（ct DNA）复合物与丙酰吖啶（PA）的相互作用，pH 值为 6.8。（H1-ct DNA）PA 复合物的 Stern-Volmer 图表明，在三个不同温度下，有两组具有不同结合亲和力的结合位点。热力学参数（ΔH°<0 和 ΔS°<0）表明，氢键和范德华力在药物与 H1-ct DNA 结合中起主要作用。在吖啶橙和溴化乙锭存在下，PA 与 ctDNA 以及（H1-ct-DNA）之间的相互作用在三元体系中表现出两种不同的相互作用行为。根据紫外吸收光谱和熔点（Tm）测量结果，PA 与 ctDNA 以及（H1-ctDNA）复合物的结合模式表明二元体系为嵌入结合，三元体系为嵌入结合与分子分数的沟槽结合。此外，PA 诱导 ctDNA 的圆二色性光谱发生可检测变化以及其粘度的变化。所有实验结果均证明，PA 与 ctDNA 以及（H1-ctDNA）复合物作为二元和三元体系的嵌入结合必须占主导地位。实验数据得到的结果与分子建模一致，确定了 PA 在没有和存在组蛋白 H1 时与 ctDNA 的结合位点。
