Influence of azide incorporation on binding affinity by small papain inhibitors

A.E.M. Wammes, T.G. Hendriks, H.I.V. Amatdjais-Groenen, M.A. Wijdeven, J.C.M. van Hest, F.L. Van Delft, T. Ritschel, F.P.J.T. Rutjes

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)5593-5603
Number of pages11
JournalBioorganic & Medicinal Chemistry
Volume22
Issue number20
DOIs
Publication statusPublished - 15 Oct 2014
Externally publishedYes

Keywords

  • Azides
  • Biosensors
  • Docking study
  • Papain inhibitors
  • Strain-promoted cycloaddition

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