Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA...

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Bibliographic Details
Published in:Angewandte Chemie 2015-08, Vol.127 (35), p.10382-10386
Main Authors: Perna, Anna M., Rodrigues, Tiago, Schmidt, Thomas P., Böhm, Manja, Stutz, Katharina, Reker, Daniel, Pfeiffer, Bernhard, Altmann, Karl-Heinz, Backert, Steffen, Wessler, Silja, Schneider, Gisbert
Format: Article
Language:English
Subjects:
Biophysikalische Methoden
Chemische Biologie
Computergestütztes Wirkstoff-Design
Rezeptor-Ligand-Wechselwirkungen
Wirkstoff-Design
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Summary:Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity. Der derzeit beste seiner Klasse ist ein Inhibitor von Helicobacter pylori HtrA, der durch fragmentbasiertes De‐novo‐Design und Analogasynthese ermittelt wurde. So lassen sich neue chemische Prototypen rasch ermitteln, und der neue Inhibitor ist ein derartiges innovatives Hilfsmittel für die chemische Biologie und eine mögliche Leitstruktur für die Suche nach Tumortherapeutika und Antiinfektiva.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201504035