Natural diterpenoids isolated-interaction-phenotypic target characterization: An idea performed with Daphne genkwa and Wikstroemia chamaedaphne bud extract.

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-10-06 DOI:10.1016/j.bioorg.2025.109065

Shi-Fei Li, De-Ling Chen, Ya-Ting Li, Li-Wei Zhang

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Abstract

In this study, twenty-two diterpenoids (including two unreported structures) were isolated and identified from the buds of Daphne genkwa and Wikstroemia chamaedaphne. Molecular docking analysis revealed that this series of compounds could stably bind to the active site of Cdc42 protein (-6.47 to -10.39 kcal/mol), with their binding energies showing significant correlation to structural features. Spectroscopic experiments confirmed that the compounds could bind to Cdc42 and alter its microenvironment. Cellular assays demonstrated that some compounds exhibited selective cytotoxicity against RAW264.7/HepG2/4T1 cells (lowest IC₅₀ 2.25 μM). CETSA verification showed that compound 6 could enhance the thermal stability of Cdc42 (∆Tm >5 °C), suggesting Cdc42 as a potential antitumor target for this compound. In conclusion, the interactions between these 22 compounds and Cdc42 protein were systematically investigated by using an "isolated-interaction-phenotypic target characterization" strategy. These findings not only established a crucial foundation for elucidating the antitumor mechanisms mediated by diterpenoid-Cdc42 interactions but also provided a practical methodological framework for natural product-based drug discovery.

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分离的天然二萜类化合物-相互作用-表型目标表征：用芫花和芫花提取物进行的想法。

从芫花和芫花的芽中分离鉴定了22个二萜类化合物（包括两个未报道的结构）。分子对接分析表明，该系列化合物能稳定结合Cdc42蛋白的活性位点（-6.47 ~ -10.39 kcal/mol），其结合能与结构特征有显著的相关性。光谱实验证实，这些化合物可以与Cdc42结合并改变其微环境。细胞实验表明，部分化合物对RAW264.7/HepG2/4T1细胞具有选择性细胞毒性（最低IC50为2.25 μM）。CETSA验证表明，化合物6可以增强Cdc42的热稳定性（∆Tm >5°C），提示Cdc42是该化合物潜在的抗肿瘤靶点。总之，采用“分离-相互作用-表型靶标表征”策略，系统地研究了这22种化合物与Cdc42蛋白之间的相互作用。这些发现不仅为阐明二萜- cdc42相互作用介导的抗肿瘤机制奠定了重要基础，而且为基于天然产物的药物开发提供了实用的方法框架。

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

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.