Binding Studies and Quantitative Structure-Activity Relationship of 3-Amino-1H-Indazoles as Inhibitors of GSK3β

Julio Caballero, Szymon Zilocchi, William Tiznado, Simona Collina, Daniela Rossi

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Docking of 3-amino-1H-indazoles complexed with glycogen synthase kinase 3 beta (GSK3β) was performed to gain insight into the structural requirements and preferred conformations of these inhibitors. The study was conducted on a selected set of 57 compounds with variation in structure and activity. We found that the most active compounds established three hydrogen bonds with the residues of the hinge region of GSK3β, but some of the less active compounds have other binding modes. In addition, models able to predict GSK3β inhibitory activities (IC 50) of the studied compounds were obtained by 3D-QSAR methods CoMFA and CoMSIA. Ligand-based and receptor-guided alignment methods were utilized. Adequate R 2 and Q 2 values were obtained by each method, although some striking differences existed between the obtained contour maps. Each of the predictive models exhibited a similar ability to predict the activity of a test set. The application of docking and quantitative structure-activity relationship together allowed conclusions to be drawn for the choice of suitable GSK3β inhibitors. Active 3-amino-1H-indazoles interact with hinge region of GSK3β, but the less active compounds cannot establish this interaction.

Original languageEnglish
Pages (from-to)631-641
Number of pages11
JournalChemical Biology and Drug Design
Volume78
Issue number4
DOIs
Publication statusPublished - Oct 2011

Keywords

  • CoMSIA
  • GSK3β
  • Glycogen synthase kinase
  • Molecular docking
  • Quantitative structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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