Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening |
| |
| Authors: | Elena M. Loi,Tihomir Tomaš ič ,Cyril Balsollier,Kevin van Eekelen,Matjaž Weiss,Martina Gobec,Matthew G. Alteen,David J. Vocadlo,Roland J. Pieters,Marko Anderluh |
| |
| Affiliation: | 1.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (E.M.L.); (T.T.); (M.W.); (M.G.);2.Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; (C.B.); (K.v.E.); (R.J.P.);3.Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; (M.G.A.); (D.J.V.) |
| |
| Abstract: | O-GlcNAcylation is an essential post-translational modification installed by the enzyme O-β-N-acetyl-d-glucosaminyl transferase (OGT). Modulating this enzyme would be extremely valuable to better understand its role in the development of serious human pathologies, such as diabetes and cancer. However, the limited availability of potent and selective inhibitors hinders the validation of this potential therapeutic target. To explore new chemotypes that target the active site of OGT, we performed virtual screening of a large library of commercially available compounds with drug-like properties. We purchased samples of the most promising virtual hits and used enzyme assays to identify authentic leads. Structure-activity relationships of the best identified OGT inhibitor were explored by generating a small library of derivatives. Our best hit displays a novel uridine mimetic scaffold and inhibited the recombinant enzyme with an IC50 value of 7 µM. The current hit represents an excellent starting point for designing and developing a new set of OGT inhibitors that may prove useful for exploring the biology of OGT. |
| |
| Keywords: | O-GlcNAc transferase OGT inhibitors virtual screening |
|
|
