Fragment-Based DeNovo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted denovo 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 denovo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity. The current best-in-class inhibitor of Helicobacter pylori HtrA was discovered using fragment-based denovo design and hit expansion. This combination allows rapid prototyping of new chemical entities, and the new inhibitor can be seen as a pioneering tool for chemical biology and potential lead structure for anti-cancer and anti-infective drug discovery.