Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis.
Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis.
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DOI：
10.3390/molecules22060891
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发表时间：
2017-05-27
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Chen C;Lu Y;Siu HM;Guan J;Zhu L;Zhang S;Yue J;Zhang L
自噬是一种基本的细胞降解过程，对细胞稳态至关重要，功能失调的自噬与多种人类疾病（如癌症）有关。一些自噬化学调节剂已经应用于一些临床前或临床试验中，用于治疗这些自噬相关疾病，特别是癌症。小分子液泡素-1有效且可逆地抑制内核体-溶酶体运输和自噬体-溶酶体融合，但液泡素-1介导的自噬抑制的分子机制尚不清楚。在这里，我们首先进行了虚拟药物筛选，并确定了14个液泡蛋白-1类似物作为自噬抑制剂。在这些虚拟筛选结果的基础上，我们进一步设计合成了17个液泡素-1类似物，发现其中13个是自噬抑制剂，有几个与液泡素-1一样有效。综上所述，这些研究扩大了有用的自噬抑制剂的范围，揭示了液泡素-1类似物的构效关系，为今后开发高效的液泡素-1类似物和鉴定液泡素-1的分子靶点提供了依据。
Autophagy is a fundamental cellular degradation process which is essential for cell homeostasis, and dysfunctional autophagy has been associated with a variety of human diseases, such as cancer. Several autophagy chemical modulators have been applied in a number of preclinical or clinical trials against these autophagy related diseases, especially cancer. Small molecule vacuolin-1 potently and reversibly inhibits both endosomal-lysosomal trafficking and autophagosome-lysosome fusion, yet the molecular mechanisms underlying vacuolin-1 mediated autophagy inhibition remain unknown. Here, we first performed the virtual drug screening and identified 14 vacuolin-1 analogues as autophagy inhibitors. Based on these virtual screening results, we further designed and synthesized 17 vacuolin-1 analogues, and found that 13 of them are autophagy inhibitors and a couple of them are as potent as vacuolin-1. In summary, these studies expanded the pool of useful autophagy inhibitors and reveal the structural-activity relationship of vacuolin-1 analogues, which is useful for future development of vacuolin-1 analogues with high potency and for identification of the molecular targets of vacuolin-1.
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影响因子：
13.3
作者：
Lu Y;Dong S;Hao B;Li C;Zhu K;Guo W;Wang Q;Cheung KH;Wong CW;Wu WT;Markus H;Yue J
通讯作者：
Yue J
DOI：
10.1073/pnas.0631766100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Feng, Y;Yu, S;Kirchhausen, T
通讯作者：
Kirchhausen, T
影响因子：
4
作者：
Eskelinen, Eeva-Liisa
通讯作者：
Eskelinen, Eeva-Liisa
影响因子：
3.5
作者：
Sano, Osamu;Kazetani, Kenichi;Iwata, Hidehisa
通讯作者：
Iwata, Hidehisa
影响因子：
50.3
作者：
Degenhardt, Kurt;Mathew, Robin;White, Eileen
通讯作者：
White, Eileen