Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β

摘要: Zinc metalloproteinases meprin α and β are implicated in a variety of diseases, such as fibrosis, inflammation neurodegeneration, however, there no selective small molecule inhibitors that would allow to study their role these processes. To address this lack molecular tools, we have developed high throughput screening assays enable discovery both screened collection well characterized pharmaceutical agents (library pharmaceutically active compounds, n = 1,280 compounds). Two compounds (PPNDS, NF449) confirmed activity selectivity for β. Kinetic studies revealed competitive (PPNDS) mixed competitive/noncompetitive (NF449) inhibition mechanisms suggesting binding occurs site. Both PPNDS NF449 exhibited low nanomolar IC50 Ki values making them the most potent reported date. These results demonstrate ability identify discard artifacts primary screening. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 396–406, 2014.