通过结构修饰降低卡博赞替尼在肾癌治疗中的毒性。

IF 1.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Jiaxiang Guo, Xiaotao Yin, Yongliang Lu, Yu Yang
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引用次数: 0

摘要

背景和目的:Cabozantinib是一种酪氨酸激酶抑制剂(TKI),广泛用于肾细胞癌(RCC)治疗,但经常引起严重的副作用,如骨髓抑制、免疫抑制和血管病变。本研究旨在确定cabozantinib治疗疗效和不良反应的关键蛋白靶点,并探索结构修饰以降低毒性同时保持疗效。方法:采用非随机计算方法,使用SwissTargetPrediction和ChemBL数据库筛选400个潜在的蛋白靶点。通过分子对接和构效关系(SAR)分析来评估cabozantinib与确定的靶标之间的相互作用,重点关注导致毒性的结构元素。结果:确定了三个主要蛋白与卡博赞替尼的抗肿瘤作用有关,而另外三个与它的副作用有关。对接分析显示,cabozantinib中的甲氧基苯基与毒性相关蛋白形成不良氢键。通过最小化该区域的氢键来调节这些脱靶相互作用可以显著减少副作用。结论:这些发现为cabozantinib的双重作用提供了结构性的见解,并为TKI设计提供了优化策略,为更安全、更有效的RCC治疗提供了途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications.

Background and objectives: Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angiopathy. This study aims to identify key protein targets responsible for the therapeutic efficacy and adverse reactions of cabozantinib and to explore structural modifications to reduce toxicity while preserving efficacy.

Methods: A non-randomized computational approach was employed, screening 400 potential protein targets using SwissTargetPrediction and ChemBL databases. Molecular docking and Structure-Activity Relationship (SAR) analysis were performed to assess interactions between cabozantinib and identified targets, focusing on structural elements contributing to toxicity.

Results: Three primary proteins were identified as responsible for the anti-tumor effects of cabozantinib, while three others were linked to its side effects. Docking analysis revealed that the methoxyphenyl group in cabozantinib formed undesirable hydrogen bonds with toxicity-related proteins. Modulating these off-target interactions by minimizing hydrogen bonding in this region could significantly reduce adverse effects.

Conclusion: These findings provide structural insights into cabozantinib's dual effects and suggest optimization strategies for TKI design, offering a pathway toward safer and more effective RCC treatments.

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来源期刊
Medicinal Chemistry
Medicinal Chemistry 医学-医药化学
CiteScore
4.30
自引率
4.30%
发文量
109
审稿时长
12 months
期刊介绍: Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.
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