Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA
- Perna, Anna M.
Schmidt, Thomas P.
- Angewandte Chemie International Edition. August 24, 2015, Vol. 54 Issue 35, p10244, 5 p.
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- Byline: , , Thomas P. Schmidt, Manja Bohm, Katharina Stutz, Daniel Reker, Bernhard Pfeiffer, Karl-Heinz Altmann, Steffen Backert, Silja Wessler, Gisbert Schneider Keywords: biophysical methods; chemical biology; computer-assisted drug design; drug design; receptor-ligand interactions 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. Author Affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich (Switzerland) Department of Molecular Biology, Universitat Salzburg (Austria) Department of Biology, Universitat Erlangen-Nurnberg (Germany) Article Note: This research was financially supported by a grant from the OPO Foundation, Zurich. The Chemical Computing Group and Inte:Ligand provided software licenses. The work of S.B. is supported by SFB-796 (project B10). The work of S.W. is supported by a grant P-24074 from the Austrian Science Fund (FWF). Camilla Pimenta and Sarah Haller are acknowledged for technical support. These authors contributed equally to the work. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): miscellaneous_information
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- Gale OneFile: Health and Medicine
- Angewandte Chemie International Edition
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