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Structure based drug design of inhibitors of the CD23 and immunoglobulin E interaction
Author(s) -
Pang Marie Oy Yee,
McDonnell James,
Beavil Andrew
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1015.7
Subject(s) - immunoglobulin e , förster resonance energy transfer , cd23 , chemistry , surface plasmon resonance , antibody , allergy , computational biology , pharmacology , biophysics , biochemistry , immunology , fluorescence , medicine , nanotechnology , biology , materials science , physics , quantum mechanics , nanoparticle
The binding of immunoglobulin E (IgE) to its low affinity receptor, CD23, has been implicated in a multitude of mechanisms underlying allergic asthma. The aim of this study is to develop inhibitors of the CD23‐IgE interaction, which may be a promising therapeutic approach for allergy. A computational approach was adopted to design a 5000 compound library with favourable physicochemical properties and attributes of protein‐protein inhibitors. Subsequently, a novel competitive screening assay based on time‐resolved fluorescence resonance energy transfer (TR‐FRET) was developed, optimised and utilised to screen the compounds. The assay was robust over the screening period and replicates of the compounds were reproducible. Setting a “hit” threshold of >;35% inhibition led to a “hit” rate of 1.8% (n=92). Validation of “hits” by TR‐FRET titrations revealed two compounds with low micromolar K i values. Surface plasmon resonance titrations confirmed specific binding of these compounds to IgE. Structural studies involving crystallography and nuclear magnetic resonance have been used to identify binding sites. The work presented in this study may potentially lead to the identification and development of inhibitors of the CD23‐IgE interaction to treat allergic asthma.