Premium
Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC‐SIGN
Author(s) -
Aretz Jonas,
Baukmann Hannes,
Shanina Elena,
Hanske Jonas,
Wawrzinek Robert,
Zapol'skii Viktor A.,
Seeberger Peter H.,
Kaufmann Dieter E.,
Rademacher Christoph
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701943
Subject(s) - druggability , heteronuclear single quantum coherence spectroscopy , dc sign , drug discovery , chemistry , computational biology , fragment (logic) , binding site , small molecule , mycobacterium tuberculosis , stereochemistry , combinatorial chemistry , biochemistry , biology , nuclear magnetic resonance spectroscopy , tuberculosis , genetics , medicine , computer science , antigen , gene , dendritic cell , programming language , pathology
Abstract DC‐SIGN is a cell‐surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis . Multiple attempts to develop inhibitors of the underlying carbohydrate–protein interactions have been undertaken in the past fifteen years. Still, drug‐like DC‐SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent‐exposed carbohydrate‐binding site. Herein, we report on a parallel fragment screening against DC‐SIGN applying SPR and a reporter displacement assay, which complements previous screenings using 19 F NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1 H– 15 N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug‐like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC‐SIGN inhibitors.