Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B

Bioorg Med Chem Lett. 2013 Oct 15;23(20):5619-23. doi: 10.1016/j.bmcl.2013.08.040. Epub 2013 Aug 14.

Abstract

Сalix[4]arenes bearing methylenebisphosphonic or hydroxymethylenebisphosphonic acid fragments at the wide rim of the macrocycle were studied as inhibitors of PTP1B. Some of the inhibitors showed IC50 values in the micromolar range and good selectivity in comparison with other protein tyrosine phosphatases such as TC-PTP, PTPβ, LAR, and CD45. Kinetic studies indicated that the calix[4]arene derivatives influence PTP1B activity as slow-binding inhibitors. Based on molecular docking results, the binding modes of the macrocyclic bisphosphonates in the active centre of PTP1B are discussed.

Keywords: Calixarene; Inhibition; Methylenebisphosphonic acid; Molecular docking; Protein tyrosine phosphatase 1B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calixarenes / chemistry*
  • Diphosphonates / chemical synthesis
  • Diphosphonates / chemistry*
  • Diphosphonates / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Phenols / chemistry*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism

Substances

  • Diphosphonates
  • Enzyme Inhibitors
  • Phenols
  • calix(4)arene
  • Calixarenes
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1