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Pharmacophore Nanoarrays on DNA Origami Substrates as a Single‐Molecule Assay for Fragment‐Based Drug Discovery
Author(s) -
Kielar Charlotte,
Reddavide Francesco V.,
Tubbenhauer Stefan,
Cui Meiying,
Xu Xiaodan,
Grundmeier Guido,
Zhang Yixin,
Keller Adrian
Publication year - 2018
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.201806778
Subject(s) - pharmacophore , benzamidine , drug discovery , chemistry , combinatorial chemistry , small molecule , molecule , denticity , nanotechnology , stereochemistry , computational biology , crystallography , materials science , biology , biochemistry , enzyme , organic chemistry , crystal structure
The rational combination of techniques from the fields of nanotechnology, single molecule detection, and lead discovery could provide elegant solutions to enhance the throughput of drug screening. We have synthesized nanoarrays of small pharmacophores on DNA origami substrates that are displayed either as individual ligands or as fragment pairs and thereby reduced the feature size by several orders of magnitude, as compared with standard microarray techniques. Atomic force microscopy‐based single‐molecule detection allowed us to distinguish potent protein–ligand interactions from weak binders. Several independent binding events, that is, strong, weak, symmetric bidentate, and asymmetric bidentate binding are directly visualized and evaluated. We apply this method to the discovery of bidentate trypsin binders based on benzamidine paired with aromatic fragments. Pairing of benzamidine with the dye TAMRA results in tenfold enhancement of the trypsin binding yield.