Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis
AbstractAutophagy 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. View Full-Text
- Supplementary File 1:
PDF-Document (PDF, 1603 KB)
Externally hosted supplementary file 1
Share & Cite This Article
Chen, C.; Lu, Y.; Siu, H.M.; Guan, J.; Zhu, L.; Zhang, S.; Yue, J.; Zhang, L. Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis. Molecules 2017, 22, 891.
Chen C, Lu Y, Siu HM, Guan J, Zhu L, Zhang S, Yue J, Zhang L. Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis. Molecules. 2017; 22(6):891.Chicago/Turabian Style
Chen, Chang; Lu, Yingying; Siu, Ho Ming; Guan, Jintao; Zhu, LongChao; Zhang, Shuang; Yue, Jianbo; Zhang, Liangren. 2017. "Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis." Molecules 22, no. 6: 891.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.