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- Title
Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.
- 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
- 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.
- Subjects
HELICOBACTER pylori; SMALL molecules; CHEMICAL biology; BIOPHYSICS; BIOACTIVE compounds
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 35, p10382
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201504035