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Fragment‐Based De Novo Design Reveals a Small‐Molecule Inhibitor of Helicobacter Pylori HtrA |
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| Authors: | Thomas P. Schmidt Dr. Manja Böhm Katharina Stutz Daniel Reker Dr. Bernhard Pfeiffer Prof. Dr. Karl‐Heinz Altmann Prof. Dr. Steffen Backert Prof. Dr. Silja Wessler Prof. Dr. Gisbert Schneider |
| Affiliation: | 1. Department of Molecular Biology, Universit?t Salzburg (Austria);2. Department of Biology, Universit?t Erlangen‐Nürnberg (Germany);3. Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir‐Prelog‐Weg 4, 8093 Zürich (Switzerland) |
| 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. |
| Keywords: | biophysical methods chemical biology computer‐assisted drug design drug design receptor– ligand interactions |