dc.contributor.author
Liese, Susanne
dc.contributor.author
Netz, Roland R.
dc.date.accessioned
2020-01-15T10:58:42Z
dc.date.available
2020-01-15T10:58:42Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/26400
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-26160
dc.description.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.
en
dc.format.extent
18 Seiten
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
multivalency
en
dc.subject
binding affinity
en
dc.subject
pathogen inhibition
en
dc.subject
statistical mechanics modeling
en
dc.subject
ligand design
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::530 Physik::530 Physik
dc.title
Quantitative prediction of multivalent ligand–receptor binding affinities for influenza, cholera, and anthrax inhibition
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1021/acsnano.7b08479
dcterms.bibliographicCitation.journaltitle
ACS nano
dcterms.bibliographicCitation.number
5
dcterms.bibliographicCitation.pagestart
4140
dcterms.bibliographicCitation.pageend
4147
dcterms.bibliographicCitation.volume
12
dcterms.bibliographicCitation.url
https://doi.org/10.1021/acsnano.7b08479
refubium.affiliation
Physik
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.issn
1936-0851
dcterms.isPartOf.eissn
1936-086X