Virtual Screening and Biological Evaluation of Natural Products as Novel VPS34 Inhibitors that Modulate Autophagy.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2024-11-22 DOI:10.1002/cmdc.202400580

Xiaowen Feng, Baoming Wu, Hanyang Xu, Chu Chen, Jiqing Ye

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Abstract

VPS34 is a sole member of class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation, making it an interesting target for cancer treatment. Here, we investigated 5,774 natural products using structure-based virtual screening against human VPS34. 10 natural products identified by virtual screening were purchased and tested in VPS34 ADP-Glo assay, yielding several potential VPS34 inhibitors. Amongst, Salvianolic acid A (4) and Ellagic acid (8) inhibited VPS34 with IC50 values of 2.46 and 3.12 uM, respectively, more potent than the positivity control 3-MA. Moreover, in vitro assays demonstrated that both of the compounds suppressed vesicle trafficking in cell-based assay. Significantly, Salvianolic acid (4) effectively prevented autophagy in Hela cells induced either by starvation or Rapamycin, an mTOR inhibitor. In addition, in silico analysis was done to elucidate the binding mechanisms of the ligand in complex with VPS34. Overall, this study highlights the efficacy of structure-based virtual screening and presents several natural products as VPS34 inhibitors that modulate autophagy.

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作为新型 VPS34 抑制剂调节自噬的天然产品的虚拟筛选和生物学评估

VPS34 是 III 类磷酸肌醇 3- 激酶的唯一成员，参与内体转运和自噬体的形成，因此是治疗癌症的一个有趣靶点。在此，我们利用基于结构的虚拟筛选技术，针对人VPS34研究了5774种天然产品。我们购买了 10 种通过虚拟筛选确定的天然产物，并在 VPS34 ADP-Glo 试验中进行了测试，结果发现了几种潜在的 VPS34 抑制剂。其中，丹酚酸 A（4）和鞣花酸（8）对 VPS34 的抑制作用 IC50 值分别为 2.46 和 3.12 uM，比阳性对照 3-MA 更强。此外，体外试验表明，在基于细胞的试验中，这两种化合物都抑制了囊泡的贩运。值得注意的是，丹酚酸（4）能有效阻止饥饿或雷帕霉素（一种 mTOR 抑制剂）诱导的 Hela 细胞自噬。此外，研究人员还进行了硅学分析，以阐明配体与 VPS34 复合物的结合机制。总之，这项研究强调了基于结构的虚拟筛选的功效，并提出了几种可调节自噬的天然产物作为 VPS34 抑制剂。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.