Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor

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• 作者：Umer Rashid^a ; ^b ; Iram Batool^a ; Abdul Wadood^c ; Ajmal Khan^d ; Zaheer ul-Haq^d ; Muhammad Iqbal Chaudhary^d ; Farzana Latif Ansari^a ; ^{fla_qau@yahoo.com}
• 关键词：Urease inhibitors ; Structure-based virtual screening ; Monastrol ; Dihydropyrimidines ; Docking
• 刊名：Journal of Molecular Graphics and Modelling
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：43
• 期：Complete
• 页码：47-57
• 全文大小：1539 K

文摘

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 ) 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.