title: Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.
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.
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Anna M
authors.initials: AM
authors.lastname: Perna
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: Department of Molecular Biology, Universität Salzburg (Austria).
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Schmidt
authors.affiliation: Department of Biology, Universität Erlangen-Nürnberg (Germany).
authors.forename: Manja
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Katharina
authors.initials: K
authors.lastname: Stutz
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Daniel
authors.initials: D
authors.lastname: Reker
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pfeiffer
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Department of Biology, Universität Erlangen-Nürnberg (Germany).
authors.forename: Steffen
authors.initials: S
authors.lastname: Backert
authors.affiliation: Department of Molecular Biology, Universität Salzburg (Austria).
authors.forename: Silja
authors.initials: S
authors.lastname: Wessler
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland). gisbert.schneider@pharma.ethz.ch.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D017076:Computer-Aided Design; D015195:Drug Design; D055808:Drug Discovery; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008024:Ligands; D010447:Peptide Hydrolases / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D010447:Peptide Hydrolases
keywords: biophysical methods; chemical biology; computer-assisted drug design; drug design; receptor-ligand interactions