Induced fit conformational changes of a "reversed amidine" heterocycle: Optimized interactions in a DNA minor groove complex
Induced fit conformational changes of a "reversed amidine" heterocycle: Optimized interactions in a DNA minor groove complex
复制标题
DOI：
10.1021/ja069003n
复制
发表时间：
2007-05-02
影响因子：
15
通讯作者：
Wilson, W. David
中科院分区：
文献类型：
--
作者：
Munde, Manoj;Lee, Michael;Wilson, W. David
为了更好地理解杂环阳离子识别DNA小沟的分子基础，制备了一系列“反脒”取代的杂环。用于靶向小沟的脒衍生物具有连接到中心杂环系统的脒碳，而在相反取向中，脒氮提供连接。反向系统具有较大的二面角以及相对于脒与凹槽的修改的空间关系。由于大的二面角，相对于类似的脒，反向脒应该具有降低的与DNA的结合。在足迹法、圆二色性（CD）、生物传感器-表面等离子体共振（SPR）和等温滴定量热（ITC）实验中观察到这种减少，DB 613具有中心苯基-呋喃-苯基杂环系统。当吡咯（DB 884）取代呋喃时，未观察到还原。对一些衍生物的分析确定吡咯和反向脒基团上的末端苯基取代基是DB 884强结合的关键组分。ITC和SPR比较表明，DB 884的更好的结合是由于更有利的结合焓，并且它与DNA的解离非常慢。结合到AATT位点的DB 884的晶体学分析显示，如CD溶液研究所示，该化合物以1：1的复合物结合在小沟中。令人惊讶的是，与脒衍生物不同，DB 884的吡咯-NH与AATT位点的中心T形成H-键，这解释了吡咯驱动的强结合。结构的结果和分子模拟研究提供了相关的脒和反脒类似物的结合亲和力的差异的解释。
To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system, whereas in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site shows that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy-driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogues.