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.
Xiaodong Dou  1 ,  Lan Jiang  1 ,  Yanxing Wang  1 ,  Hongwei Jin  1 ,  Zhenming Liu  2 ,  Liangren Zhang  3
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
PMID: 29208522 DOI: 10.1016/j.bmcl.2017.11.036
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.
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