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

TitleFragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.
Publication TypeJournal Article
Year of Publication2015
AuthorsAM Perna, T Rodrigues, TP Schmidt, M Böhm, K Stutz, D Reker, B Pfeiffer, K-H Altmann, S Backert, S Wessler, and G Schneider
JournalAngewandte Chemie International Edition
Volume54
Start Page10244
Issue35
Pagination10244 - 10248
Date Published08/2015
Abstract

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.

DOI10.1002/anie.201504035
Short TitleAngewandte Chemie International Edition