Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors

Mol Divers. 2017 May;21(2):385-405. doi: 10.1007/s11030-016-9724-5. Epub 2017 Jan 21.


The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed. A five-point pharmacophore model was built consisting of a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and two rings (RR). An atom-based 3D quantitative structure-activity relationship (QSAR) model showed good correlative and satisfactory predictive abilities (training set [Formula: see text]; test set: [Formula: see text]; whole data set: stability [Formula: see text]). Virtual screening experiments revealed that selective GSK-3 inhibitors are ranked preferentially by Hypo-1, but fail to retrieve nonselective compounds. The pharmacophore and 3D QSAR models can provide assistance to design novel, potential GSK-3 inhibitors with high potency and selectivity pattern, with potential application for the treatment of GSK-3-driven diseases. A class of purine nucleoside antileukemic drugs was identified as potential inhibitor of GSK-3, suggesting the reassessment of the target range of these drugs.

Keywords: Atom-based 3D QSAR; Benchmarking validation data set; GSK-3 inhibitors; Pharmacophore; Repurposing.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Repositioning*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Leukemia / drug therapy


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Glycogen Synthase Kinase 3