关于抗疟药氯喹与双链 DNA 相互作用的核碱基特异性理解,The Journal of Physical Chemistry B

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关于抗疟药氯喹与双链 DNA 相互作用的核碱基特异性理解
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-04-11 , DOI: 10.1021/acs.jpcb.2c08265
Asim Bisoi ₁ , Sunipa Sarkar ₁ , Tithi Lai ₁ , Prashant Chandra Singh ₁

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药物的抗疟作用与寄生虫 DNA 的相互作用密切相关。因此，在本研究中，研究了一种重要的抗疟药物氯喹 (CLQ) 与具有纯腺嘌呤 (A)-胸腺嘧啶 (T) 和纯胞嘧啶 (C)-鸟嘌呤 (G) 的六种不同 DNA 序列的相互作用。以及混合核碱基，以实现抗疟药物与 DNA 结合的核碱基水平信息，以及使用不同的光谱方法和分子动力学模拟技术结合诱导 DNA 的稳定/去稳定。此外，还用CLQ的类似物4-氨基-7-氯喹啉(7CLQ)进行了实验，以了解CLQ的喹啉环和侧链在与不同DNA序列结合中的作用。CLQ 与任意 DNA 序列的结合效率均高于 7CLQ，表明 CLQ 上电荷的存在在 DNA 结合中发挥着重要作用。数据表明药物的结合以及诱导的 DNA 稳定性很大程度上取决于核碱基的性质和排列。一般来说，CLQ与纯CG DNA的结合高于与纯AT DNA的结合；此外，它更喜欢 CG/AT 的交替顺序，而不是双链 DNA 中的连续核碱基。CLQ 主要容纳在 AT DNA 的小沟中，并且倾向于主要与腺嘌呤核碱基形成氢键。与AT DNA相反，CLQ侵入大沟和小沟，但它主要适应CG DNA的大沟。CLQ 主要与 CG DNA 大沟中的鸟嘌呤和小沟中的胞嘧啶形成氢键，与 AT DNA 相比，这增强了 CLQ 的结合，并诱导 CG DNA 更高的稳定性。获得的有关负责 CLQ 相互作用的官能团的分子水平信息以及核碱基化学性质的作用及其对 CLQ 与 DNA 结合的排序可能有助于全面理解其作用机制。

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Nucleobase Specific Understanding about the Interaction of Antimalarial Drug Chloroquine with Duplex DNA

Antimalarial action of a drug is closely associated with the interaction with the parasite’s DNA. Hence, in this study, the interaction of an important antimalarial drug, chloroquine (CLQ), has been investigated with six different sequences of DNA having pure adenine (A)–thymine (T) and pure cytosine (C)–guanine (G) as well as mixed nucleobases to achieve the nucleobase level of information in the binding of antimalarial drug with DNA along with binding induced stabilization/destabilization of DNA using different spectroscopic methods and molecular dynamics simulation technique. Further, the experiments have been also performed with 4-amino-7-chloroquinoline (7CLQ), an analogue of CLQ, to understand the role of the quinoline ring and side chain of CLQ in the binding with different sequences of DNA. The binding efficiency of CLQ with any sequence of DNA is higher than 7CLQ suggesting that the presence of charge on CLQ plays a prominent role in DNA binding. The data suggest that the binding of drug as well as induced stabilization of DNA depends significantly on the nature as well as the arrangement of the nucleobases. In general, the binding of CLQ with pure CG DNA is higher than with pure AT DNA; moreover, it prefers an alternate order of CG/AT than continual nucleobases in duplex DNA. CLQ predominately accommodates in the minor groove of AT DNA and prefers to form hydrogen bond mostly with the adenine nucleobase. In contrast to AT DNA, CLQ intrudes into the both major and minor grooves, but it is primarily accommodated into the major groove of CG DNA. CLQ forms a hydrogen bond mainly with guanine in the major groove and cytosine in the minor groove of CG DNA which enhances the binding of CLQ compared to AT DNA as well as induces higher stabilization in CG DNA. The molecular level information obtained about the functional group responsible for the interaction of CLQ as well as the role of chemical nature of nucleobases along with its ordering on the binding of CLQ with DNA may be useful in comprehensive understanding of its action mechanism.

更新日期：2023-04-11

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