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

• Published in: Angewandte Chemie Vol. 127; no. 35; pp. 10382 - 10386
• Main Authors: Perna, Anna M, Rodrigues, Tiago, Schmidt, Thomas P, Bohm, Manja, Stutz, Katharina, Reker, Daniel, Pfeiffer, Bernhard, Altmann, Karl-Heinz, Backert, Steffen, Wessler, Silja, Schneider, Gisbert
• Format: Journal Article
• Language: English; German
• Published: Weinheim Wiley Subscription Services, Inc 01.08.2015
• Subjects: Binding; Biochemistry; Biology; Chemistry; Fragmentation; Helicobacter pylori; Inhibitors; Optimization; Prototyping
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201504035

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted denovo 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 denovo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity.Original Abstract: 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 fuer die chemische Biologie und eine mogliche Leitstruktur fuer die Suche nach Tumortherapeutika und Antiinfektiva.