title: Influence of azide incorporation on binding affinity by small papain inhibitors.
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.
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Angelique E M
authors: AE
authors: Wammes
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands; Computational Discovery and Design (CDD) Group, Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: Tom G
authors: TG
authors: Hendriks
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Helene I V
authors: HI
authors: Amatdjais-Groenen
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Marloes A
authors: MA
authors: Wijdeven
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Jan C M
authors: JC
authors: van Hest
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
authors: Floris L
authors: FL
authors: van Delft
authors: Computational Discovery and Design (CDD) Group, Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: tina.ritschel@radboudumc.nl.
authors: Tina
authors: T
authors: Ritschel
authors: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. Electronic address: f.rutjes@science.ru.nl.
authors: Floris P J T
authors: FP
authors: Rutjes
mesh_terms: D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010206:Papain / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D001386:Azides; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D010206:Papain
keywords: Azides; Biosensors; Docking study; Papain inhibitors; Strain-promoted cycloaddition