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Engineered modular heterocyclic-diamidines for sequence-specific recognition of mixed AT/GC base pairs at the DNA minor groove
Chemical Science ( IF 7.6 ) Pub Date : 2021-11-02 , DOI: 10.1039/d1sc04720e Pu Guo 1 , Abdelbasset A Farahat 1, 2 , Ananya Paul 1 , David W Boykin 1 , W David Wilson 1
Chemical Science ( IF 7.6 ) Pub Date : 2021-11-02 , DOI: 10.1039/d1sc04720e Pu Guo 1 , Abdelbasset A Farahat 1, 2 , Ananya Paul 1 , David W Boykin 1 , W David Wilson 1
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This report describes a breakthrough in a project to design minor groove binders to recognize any sequence of DNA. A key goal is to invent synthetic chemistry for compound preparation to recognize an adjacent GG sequence that has been difficult to target. After trying several unsuccessful compound designs, an N-alkyl-benzodiimidazole structure was selected to provide two H-bond acceptors for the adjacent GG-NH groups. Flanking thiophenes provide a preorganized structure with strong affinity, DB2831, and the structure is terminated by phenyl-amidines. The binding experimental results for DB2831 with a target AAAGGTTT sequence were successful and include a high ΔTm, biosensor SPR with a KD of 4 nM, a similar KD from fluorescence titrations and supporting competition mass spectrometry. MD analysis of DB2831 bound to an AAAGGTTT site reveals that the two unprotonated N of the benzodiimidazole group form strong H-bonds (based on distance) with the two central G-NH while the central –CH of the benzodiimidazole is close to the –C![[double bond, length as m-dash]](https://www.rsc.org/images/entities/char_e001.gif)
O of a C base. These three interactions account for the strong preference of DB2831 for a -GG- sequence. Surprisingly, a complex with one dynamic, interfacial water is favored with 75% occupancy.
中文翻译：
工程模块化杂环二脒用于 DNA 小沟混合 AT/GC 碱基对的序列特异性识别
该报告描述了设计小沟结合物以识别任何 DNA 序列的项目的突破。一个关键目标是发明用于化合物制备的合成化学，以识别难以靶向的相邻 GG 序列。在尝试了几种不成功的化合物设计后，选择了N-烷基-苯并二咪唑结构来为相邻的GG-NH基团提供两个H键受体。侧翼噻吩提供了具有强亲和力的预组织结构 DB2831，并且该结构由苯基脒封端。 DB2831 与目标 AAAGGTTT 序列的结合实验结果是成功的，包括高 Δ T m 、 KD为 4 nM 的生物传感器 SPR、来自荧光滴定的类似KD和支持竞争质谱法。对与 AAAGGTTT 位点结合的 DB2831 进行 MD 分析表明，苯并二咪唑基团的两个非质子化N与两个中心 G-NH 形成强氢键（基于距离），而苯并二咪唑的中心 –CH 靠近 –C C碱基的O。这三种相互作用解释了 DB2831 对 -GG- 序列的强烈偏好。令人惊讶的是，具有一种动态界面水的综合体以 75% 的占用率受到青睐。
更新日期：2021-11-24
O of a C base. These three interactions account for the strong preference of DB2831 for a -GG- sequence. Surprisingly, a complex with one dynamic, interfacial water is favored with 75% occupancy.
中文翻译：
工程模块化杂环二脒用于 DNA 小沟混合 AT/GC 碱基对的序列特异性识别
该报告描述了设计小沟结合物以识别任何 DNA 序列的项目的突破。一个关键目标是发明用于化合物制备的合成化学，以识别难以靶向的相邻 GG 序列。在尝试了几种不成功的化合物设计后，选择了N-烷基-苯并二咪唑结构来为相邻的GG-NH基团提供两个H键受体。侧翼噻吩提供了具有强亲和力的预组织结构 DB2831，并且该结构由苯基脒封端。 DB2831 与目标 AAAGGTTT 序列的结合实验结果是成功的，包括高 Δ T m 、 KD为 4 nM 的生物传感器 SPR、来自荧光滴定的类似KD和支持竞争质谱法。对与 AAAGGTTT 位点结合的 DB2831 进行 MD 分析表明，苯并二咪唑基团的两个非质子化N与两个中心 G-NH 形成强氢键（基于距离），而苯并二咪唑的中心 –CH 靠近 –C
C碱基的O。这三种相互作用解释了 DB2831 对 -GG- 序列的强烈偏好。令人惊讶的是，具有一种动态界面水的综合体以 75% 的占用率受到青睐。
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