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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.

SUBMITTER: Perna AM

PROVIDER: S-EPMC6311382 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Perna Anna M AM Rodrigues Tiago T Schmidt Thomas P TP Böhm Manja M Stutz Katharina K Reker Daniel D Pfeiffer Bernhard B Altmann Karl-Heinz KH Backert Steffen S Wessler Silja S Schneider Gisbert G

Angewandte Chemie (International ed. in English) 20150609 35

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 rein ...[more]

PMID: 26069090

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