Molecular design of hydroxamic acid-based derivatives as urease inhibitors of Helicobacter pylori.

Helicobacter pylori is the main causative agent of gastric cancer, especially non-cardiac gastric cancers. This bacterium relies on urease producing much ammonia to colonize the host. Herein, the study provides valuable insights into structural patterns driving urease inhibition for high-activity molecules designed via exploring known inhibitors. Firstly, an ensemble model was devised to predict the inhibitory activity of novel compounds in an automated workflow (R2 = 0.761) that combines four machine learning approaches. The dataset was characterized in terms of chemical space, including molecular scaffolds, clustering analysis, distribution for physicochemical properties, and activity cliffs. Through these analyses, the hydroxamic acid group and the benzene ring responsible for distinct activity were highlighted. Activity cliff pairs uncovered substituents of the benzene ring on hydroxamic acid derivatives are key structures for substantial activity enhancement. Moreover, 11 hydroxamic acid derivatives were designed, named mol1-11. Results of molecular dynamic simulations showed that the mol9 exhibited stabilization of the active site flap's closed conformation and are expected to be promising drug candidates for Helicobacter pylori infection and further in vitro, in vivo, and clinical trials to demonstrate in future.