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

Robinson, Elizabeth and Leung, Euphemia and Matuszek, Anna and Krogsgaard-Larsen, Niels and Furkert, Daniel and Brimble, Margaret and Richardson, Alan and Reynisson, Johannes (2014) Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation. MedIcinal Chemistry Communications, 6 . pp. 239-246. ISSN 2040-2511

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Abstract or Summary

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.

Item Type:Journal article
Keywords that describe the item:autophagy, autophagy inhibitors, Atg5-Atg16 complex
Subjects:Q Science > QD Chemistry
Divisions:Schools > Centre for Science and Primary Industries
ID Code:5775
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Deposited On:23 Jan 2018 23:28
Last Modified:23 Jan 2018 23:28

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