Large-scale virtual screening for the identification of new Helicobacter pylori urease inhibitor scaffolds

Abstract

Here, we report a structure-based virtual screening of the ZINC database (containing about five million compounds) by computational docking and the analysis of docking energy calculations followed by in vitro screening against H. pylori urease enzyme. One of the compounds selected showed urease inhibition in the low micromolar range. Barbituric acid and compounds 1a, 1d, 1e, 1f, 1g, 1h were found to be more potent urease inhibitors than the standard inhibitor hydroxyurea, yielding IC(50) values of 41.6, 83.3, 66.6, 50, 58.8, and 60 μM, respectively (IC(50) of hydroxyurea = 100 μM). 5-Benzylidene barbituric acid has enhanced biological activities compared to barbituric acid. Furthermore, the results indicated that among the substituted 5-benzylidene barbiturates, those with para substitution have higher urease inhibitor activities. This may be because the barbituric acid moiety is closer to the bimetallic nickel center in unsubstituted or para-substituted than in ortho- or meta-substituted analogs, so it has greater chelating ability.

Natural Products as a Potential Enzyme Inhibitors from Medicinal Plants

“…Furthermore, urease inhibitors might be active therapies for the cure of diseases produced by urease-dependent pathogenic microorganisms. However, the commercially accessible urease inhibitors, including hydroxamic acid derivatives, phosphorodiamidates, and imidazoles, are toxic and have low stability, feature that stop their clinical usage [29]. The main search for new, known, novel, and bioactive urease inhibitors which enhanced stability and low toxicity is necessary to improve life excellence of human beings and animals.…”

Effect of propolis in gastric disorders: inhibition studies on the growth ofHelicobacter pyloriand production of its urease

“…Antibiotic therapy or a combination of two or three drugs has been widely used for the management of these infections. However, the commercially available urease inhibitors, such as phosphorodiamidates, hydroxamic acid derivatives and imidazoles, are toxic and have poor stability, features that prevent their clinical use 7,8 . In addition to this, one of the reasons for the failure of H. pylori eradication in many countries is the increasing antibiotic resistance 2 .…”

Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening

“…Similar compounds of the new ligand from ZINC database (www.zinc.docking.org) were obtained (2150 compounds) [18,29]. The virtual docking experiments were separately performed on p53 and Hsp90 by AutoDock 4.2.…”