Charlotte Kielar; Francesco V. Reddavide; Stefan Tubbenhauer; Meiying Cui; Xiaodan Xu; Guido Grundmeier; Yixin Zhang; Adrian Keller
Angew. Chem. Int. Ed. Engl., 2018, 57(45), 14873-14877
https://doi.org/10.1002/anie.201806778

Abstract

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, i.e., strong binding, weak binding, symmetric bidentate binding, 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.