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Quantitative Prediction of Multivalent Ligand-Receptor Binding Affinities for Influenza, Cholera, and Anthrax Inhibition.

Authors
  • Liese, Susanne1, 2
  • Netz, Roland R1
  • 1 Department of Physics , Freie Universität Berlin , 14195 Berlin , Germany. , (Germany)
  • 2 Department of Mathematics , University of Oslo , 0851 Oslo , Norway. , (Norway)
Type
Published Article
Journal
ACS Nano
Publisher
American Chemical Society
Publication Date
May 22, 2018
Volume
12
Issue
5
Pages
4140–4147
Identifiers
DOI: 10.1021/acsnano.7b08479
PMID: 29474056
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Multivalency achieves strong, yet reversible binding by the simultaneous formation of multiple weak bonds. It is a key interaction principle in biology and promising for the synthesis of high-affinity inhibitors of pathogens. We present a molecular model for the binding affinity of synthetic multivalent ligands onto multivalent receptors consisting of n receptor units arranged on a regular polygon. Ligands consist of a geometrically matching rigid polygonal core to which monovalent ligand units are attached via flexible linker polymers, closely mimicking existing experimental designs. The calculated binding affinities quantitatively agree with experimental studies for cholera toxin ( n = 5) and anthrax receptor ( n = 7) and allow to predict optimal core size and optimal linker length. Maximal binding affinity is achieved for a core that matches the receptor size and for linkers that have an equilibrium end-to-end distance that is slightly longer than the geometric separation between ligand core and receptor sites. Linkers that are longer than optimal are greatly preferable compared to shorter linkers. The angular steric restriction between ligand unit and linker polymer is shown to be a key parameter. We construct an enhancement diagram that quantifies the multivalent binding affinity compared to monovalent ligands. We conclude that multivalent ligands against influenza viral hemagglutinin ( n = 3), cholera toxin ( n = 5), and anthrax receptor ( n = 7) can outperform monovalent ligands only for a monovalent ligand affinity that exceeds a core-size dependent threshold value. Thus, multivalent drug design needs to balance core size, linker length, as well as monovalent ligand unit affinity.

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