Discovery of new GSK-3ß inhibitors through structure-based virtual screening.

ABSTRACT

Glycogen synthase kinase-3ß (GSK-3ß) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3ß inhibitors, and we observed that conserved water molecules of GSK-3ß were suitable for virtual screening. We found 14 hits and D1 (IC50 of 0.71 µM) were identified. Furthermore, the neuroprotection activity of D1-D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure-activity relationship suggested that these skeletons were worthy of study as potent GSK-3ß inhibitors.