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

Bioorg Med Chem Lett. 2018 Jan 15;28(2):160-166. doi: 10.1016/j.bmcl.2017.11.036. Epub 2017 Nov 24.

Abstract

Glycogen synthase kinase-3β (GSK-3β) 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-3β inhibitors, and we observed that conserved water molecules of GSK-3β 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-3β inhibitors.

Keywords: 2D similarity search; GSK-3β; Molecular dynamics; Radiometric assay; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3 beta