title: 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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 16 Azar Ave, Tehran, Iran.
authors.forename: Homa
authors.initials: H
authors.lastname: Azizian
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Nabati
authors.forename: Amirhossein
authors.initials: A
authors.lastname: Sharifi
authors.forename: Farideh
authors.initials: F
authors.lastname: Siavoshi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Mahdavi
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D001463:Barbiturates / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology*; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001463:Barbiturates; D004791:Enzyme Inhibitors; D014510:Urease