title: Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor.
abstract: Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in-house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems.
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Umer
authors.initials: U
authors.lastname: Rashid
authors.forename: Iram
authors.initials: I
authors.lastname: Batool
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.forename: Ajmal
authors.initials: A
authors.lastname: Khan
authors.forename: Zaheer
authors.initials: Z
authors.lastname: ul-Haq
authors.forename: Muhammad Iqbal
authors.initials: MI
authors.lastname: Chaudhary
authors.forename: Farzana Latif
authors.initials: FL
authors.lastname: Ansari
mesh_terms: D001407:Bacillus / Q000201:enzymology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism; D016547:Kinesins / Q000037:antagonists & inhibitors; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000378:metabolism*; D013871:Thiones / Q000378:metabolism*; D014510:Urease / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*
chemical_list: D006877:Hydroxamic Acids; D008024:Ligands; D011743:Pyrimidines; D013871:Thiones; C006358:acetohydroxamic acid; C400223:monastrol; D014510:Urease; D016547:Kinesins