Abstract：
The biological activity of drugs is exhibited due to their interactions with bio-receptors. Dicoumarol (DIC) is a natural hydroxycoumarin and a well-known anticoagulant. DNA is the genetic material and one of the targets of numerous drugs. The interaction of DIC with calf-thymus DNA (ct-DNA) has been studied using different biophysical techniques and docking studies. The binding constant in the order of 103 to 104 M-1 was observed from spectroscopic studies. Thermodynamic studies at 4 different temperatures revealed the spontaneity of the interaction with the entropy-driven process. Marker displacement studies with competitive markers of intercalators (ethidium bromide) and groove binders (Hoechst 33258) confirmed the groove-binding nature of DIC in DNA. The groove-binding mode of DIC was complemented by different studies like viscosity measurements, DNA melting, and the effect of KI on the binding. A minor perturbation in the DNA viscosity and no significant change in the DNA melting temperature (Tm) after binding with DIC further confirms the groove binding mode. The effect of KI on the DIC and DIC-DNA system suggested the absence of DIC intercalation. The absence of significant electrostatic force was revealed from the ionic-strength effect study. Binding-induced conformational variation in ct-DNA was absent in circular dichroism studies. Molecular docking studies suggested the position of DIC within the minor groove of ct-DNA, covering three base pairs long. The outcome of this report may help in understanding the pharmacodynamics and pharmacokinetics of dicoumarol analogs and related molecules.Communicated by Ramaswamy H. Sarma.
摘要：
药物的生物活性由于它们与生物受体的相互作用而表现出来。双香豆醇(DIC)是一种天然的羟基香豆素和一种众所周知的抗凝剂。DNA是遗传物质和众多药物的靶标之一。已使用不同的生物物理技术和对接研究研究了DIC与小牛胸腺DNA（ct-DNA）的相互作用。从光谱研究中观察到103至104M-1的结合常数。在4个不同温度下的热力学研究揭示了与熵驱动过程相互作用的自发性。用嵌入剂（溴化乙锭）和凹槽结合剂（Hoechst33258）的竞争性标记进行的标记置换研究证实了DIC在DNA中的凹槽结合性质。DIC的沟槽结合模式得到了不同研究的补充，如粘度测量，DNA解链,以及KI对绑定的影响。与DIC结合后,DNA粘度的微小扰动和DNA解链温度(Tm)没有显著变化进一步证实了凹槽结合模式。KI对DIC和DIC-DNA系统的影响表明不存在DIC嵌入。离子强度效应研究表明，没有明显的静电力。在圆二色性研究中不存在ct-DNA中结合诱导的构象变异。分子对接研究表明DIC在ct-DNA小沟内的位置，覆盖三个碱基对长。本报告的结果可能有助于理解双香豆酚类似物和相关分子的药效学和药代动力学。由RamaswamyH.Sarma沟通。
