Influence of azide incorporation on binding affinity by small papain inhibitors

Bioorg Med Chem. 2014 Oct 15;22(20):5593-603. doi: 10.1016/j.bmc.2014.06.001. Epub 2014 Jun 11.

Abstract

In order to develop affinity-based biosensor platforms, appropriate ligands with a functional handle for immobilization onto a biosensor surface are required. To this end, a library of papain inhibitors was designed and synthesized, containing different azide linkers for subsequent immobilization by 'click' chemistry, in this particular case by copper-free, strain-promoted azide-alkyne cycloaddition (SPAAC). Furthermore, a molecular docking study was performed to obtain a better insight as to at which position such azide handles could be tolerated without affecting binding affinity. Although the azide moiety is small, in some cases its introduction strongly influenced the binding affinity. For one class of inhibitors a swapped binding mode was proposed to explain the results. In addition, a specific site for linker introduction was identified, which did not significantly affect the binding affinity.

Keywords: Azides; Biosensors; Docking study; Papain inhibitors; Strain-promoted cycloaddition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemistry
  • Alkynes / pharmacology*
  • Azides / chemistry
  • Azides / pharmacology*
  • Binding Sites
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Papain / antagonists & inhibitors*
  • Papain / chemistry
  • Papain / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Alkynes
  • Azides
  • Cysteine Proteinase Inhibitors
  • Ligands
  • Small Molecule Libraries
  • Papain