dc.contributor.author
Aretz, Jonas
dc.contributor.author
Wamhoff, Eike-Christian
dc.contributor.author
Hanske, Jonas
dc.contributor.author
Heymann, Dario
dc.contributor.author
Rademacher, Christoph
dc.date.accessioned
2018-06-08T03:23:20Z
dc.date.available
2015-06-12T07:46:37.594Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/15075
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-19263
dc.description.abstract
Mammalian C-type lectin receptors (CTLRS) are involved in many aspects of
immune cell regulation such as pathogen recognition, clearance of apoptotic
bodies, and lymphocyte homing. Despite a great interest in modulating CTLR
recognition of carbohydrates, the number of specific molecular probes is
limited. To this end, we predicted the druggability of a panel of 22 CTLRs
using DoGSiteScorer. The computed druggability scores of most structures were
low, characterizing this family as either challenging or even undruggable. To
further explore these findings, we employed a fluorine-based nuclear magnetic
resonance screening of fragment mixtures against DC-SIGN, a receptor of
pharmacological interest. To our surprise, we found many fragment hits
associated with the carbohydrate recognition site (hit rate = 13.5%). A
surface plasmon resonance-based follow-up assay confirmed 18 of these
fragments (47%) and equilibrium dissociation constants were determined.
Encouraged by these findings we expanded our experimental druggability
prediction to Langerin and MCL and found medium to high hit rates as well,
being 15.7 and 10.0%, respectively. Our results highlight limitations of
current in silico approaches to druggability assessment, in particular, with
regard to carbohydrate-binding proteins. In sum, our data indicate that small
molecule ligands for a larger panel of CTLRs can be developed.
en
dc.rights.uri
http://creativecommons.org/licenses/by/3.0/
dc.subject
C-type lectin receptors
dc.subject
fragment screening
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie
dc.title
Computational and experimental prediction of human C-type lectin receptor
druggability
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
Frontiers in Immunology. - 5 (2014), Artikel Nr. 323
dcterms.bibliographicCitation.doi
10.3389/fimmu.2014.00323
dcterms.bibliographicCitation.url
http://dx.doi.org/10.3389/fimmu.2014.00323
refubium.affiliation
Biologie, Chemie, Pharmazie
de
refubium.mycore.fudocsId
FUDOCS_document_000000022627
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000005043
dcterms.accessRights.openaire
open access