Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation

Abstract

Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and re-ported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were se-lected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3β enzyme and markedly activated Wnt sig-naling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall re-straint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors de-signed to inhibit the GSK3β enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.