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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 reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected 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 signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed 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.

SUBMITTER: Lee Y 

PROVIDER: S-EPMC9230645 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Lee Yuno Y   Yoon Sae-Bom SB   Hong Hyowon H   Kim Hyun Young HY   Jung Daeyoung D   Moon Byoung-San BS   Park Woo-Kyu WK   Lee Sunkyung S   Kwon Hyukjin H   Park Jihyeong J   Cho Heeyeong H  

Molecules (Basel, Switzerland) 20220614 12

Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected 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 signaling. The result of the molecular dyna  ...[more]

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