Issue 1, 2015

Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation

Abstract

Two hit compounds (14 and 62) were identified using virtual high throughput screening (vHTS) inhibiting the autophagy process in A2780 ovarian cancer cells. The expression levels of the LC3-II and p62 autophagy marker proteins were monitored using Western blotting. Preliminary structure activity relationship (SAR) study of close structural analogues revealed another active compound 38. The three active compounds were tested in the MCF-7 human breast cancer cells and severe reduction of autophagosomes formation was observed confirming the activity of the inhibitors. The docking scaffold used for the vHTS was a lipophilic cleft on the Atg5 protein, which is occupied by a phenylalanine residue in the Atg16 polypeptide. To the best of our knowledge this is the first report on inhibitors that specifically modulate autophagy by directly inhibiting autophagy specific proteins, which is significant due the role autophagy plays in a number of morbid diseases such as cancer.

Graphical abstract: Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation

Supplementary files

Article information

Article type
Concise Article
Submitted
19 Sep 2014
Accepted
31 Oct 2014
First published
03 Nov 2014

Med. Chem. Commun., 2015,6, 239-246

Author version available

Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation

E. Robinson, E. Leung, A. M. Matuszek, N. Krogsgaard-Larsen, D. P. Furkert, M. A. Brimble, A. Richardson and J. Reynisson, Med. Chem. Commun., 2015, 6, 239 DOI: 10.1039/C4MD00420E

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