Discovery and evaluation of the hybrid of bromophenol and saccharide as potent and selective protein tyrosine phosphatase 1B inhibitors

Eur J Med Chem. 2017 Jul 7:134:24-33. doi: 10.1016/j.ejmech.2017.04.004. Epub 2017 Apr 4.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC50 values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP. Moreover, the cell permeability and cellular activity of compound 10a are demonstrated respectively.

Keywords: Bromophenol; PTP1B; Permeability; Saccharide; Selectivity.

MeSH terms

  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Halogenation
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Monosaccharides / chemistry*
  • Monosaccharides / pharmacology*
  • Phenols / chemistry*
  • Phenols / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism

Substances

  • Enzyme Inhibitors
  • Monosaccharides
  • Phenols
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2