Discovery\nof Novel Nonpeptidic Proteasome Inhibitors\nUsing Covalent Virtual Screening and Biological Evaluation

Many reported proteasome inhibitors, including the three\nclinically\napproved inhibitors, bortezomib, carfilzomib, and ixazomib, have peptidic\nstructures. In this study, using a hybrid and versatile strategy for\ncovalent virtual screening by combining warhead screening and preprocessing\nwith GOLD and CovDock software that were applied to the ZINC virtual\nlibrary, we identified multiple proteasome inhibitors with new nonpeptidic\nstructural scaffolds. Proteasome inhibition assays confirmed the inhibitory\nactivities of these new compounds. These results demonstrate the effectiveness\nof our computational strategy for large-scale covalent virtual screening.\nFurthermore, these identified proteasome inhibitors may serve as starting\npoints for the development of a new class of nonpeptidic therapeutic\nagents.