Investigating the interactions of Axitinib, a tyrosine kinase inhibitor, with DNA: experimental studies, molecular docking, and molecular dynamics simulations.

IF 1.1 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Pelin Şenel, Abdullah Al Faysal, Soykan Agar, Mine Yurtsever, Ayşegül Gölcü
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Abstract

Axitinib is an oral medication classified as a second-generation tyrosine kinase inhibitor. It serves as a primary treatment for metastatic renal cell carcinoma (RCC) due to its strong affinity for DNA, which leads to the disruption of the double helix structure. This disruption ultimately halts the cell cycle and induces senescence and mitotic catastrophe in RCC cells. Consequently, investigating the mechanism by which Axitinib binds to DNA is essential for comprehending its pharmacodynamic properties and for the advancement of more effective DNA-binding therapeutics. The present study aimed to examine the interaction between Axitinib and DNA through various analytical techniques, including UV-Vis spectroscopy, thermal denaturation assays, electrochemical methods, and fluorescence emission spectroscopy. According to the electrochemical studies, the binding constant (Kb) for Axitinib was calculated to be (5.13 ± 0.28) × 104, suggesting the potential for groove binding. This finding was further supported by in-silico analyses, where molecular docking and molecular dynamics simulations indicated that the drug selectively binds to the DNA minor groove through partial intercalation, forming new hydrogen bonds with its functional groups while separating the guanine and cytosine base pairs.

研究酪氨酸激酶抑制剂阿西替尼与DNA的相互作用:实验研究、分子对接和分子动力学模拟。
阿西替尼是一种口服药物,被归类为第二代酪氨酸激酶抑制剂。它作为转移性肾细胞癌(RCC)的主要治疗方法,由于其对DNA的强亲和力,导致双螺旋结构的破坏。这种破坏最终使细胞周期停止,并在RCC细胞中诱发衰老和有丝分裂灾难。因此,研究阿西替尼与DNA结合的机制对于理解其药效学特性和开发更有效的DNA结合疗法至关重要。本研究旨在通过各种分析技术,包括紫外可见光谱、热变性测定、电化学方法和荧光发射光谱,来研究阿西替尼与DNA之间的相互作用。根据电化学研究,计算出Axitinib的结合常数(Kb)为(5.13±0.28)× 104,表明其具有凹槽结合的潜力。这一发现进一步得到了计算机分析的支持,其中分子对接和分子动力学模拟表明,该药物通过部分嵌入选择性地与DNA小凹槽结合,与其官能团形成新的氢键,同时分离鸟嘌呤和胞嘧啶碱基对。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nucleosides, Nucleotides & Nucleic Acids
Nucleosides, Nucleotides & Nucleic Acids 生物-生化与分子生物学
CiteScore
2.60
自引率
7.70%
发文量
91
审稿时长
6 months
期刊介绍: Nucleosides, Nucleotides & Nucleic Acids publishes research articles, short notices, and concise, critical reviews of related topics that focus on the chemistry and biology of nucleosides, nucleotides, and nucleic acids. Complete with experimental details, this all-inclusive journal emphasizes the synthesis, biological activities, new and improved synthetic methods, and significant observations related to new compounds.
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