BMC Seminar, Thursday, 24th November at 12:10, Room 102, Læknagarður
Speaker: Dr. Jóhannes Reynisson, Senior Researcher, School of Chemical Sciences, University of Auckland, New Zealand
Title: Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation
Short abstract: Two hit compounds (14 and 62) were identified using virtual high throughput screening (vHTS) inhibiting the autophagy process1, 2 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.3
1. Noda NN, Ohsumi Y, Inagaki F. (2009) ATG Systems from the Protein Structural Point of View. Chem. Rev. 109: 1587-1598.
2. Fujioka Y, Noda NN, Nakatogawa H, Ohsumi Y, Inagaki F. (2010) Dimeric Coiled-coil Structure of Saccharomyces cerevisiae Atg16 and Its Functional Significance in Autophagy. J. Biol. Chem. 285: 1508-1515.
3. Robinson E, Leung E, Matuszek AM, Krogsgaard-Larsen, N., Furkert, D.P., Brimble, M.A., Richardson, A. Reynisson, J. (2015) Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation. Med. Chem. Comm. 6: 239-246.