title: Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping.
abstract: An aminoquinazoline series targeting the essential bacterial enzyme GlmU (uridyltransferase) were previously reported (Biochem. J.2012, 446, 405). In this study, we further explored SAR through a combination of traditional medicinal chemistry and structure-based drug design, resulting in a novel scaffold (benzamide) with selectivity against protein kinases. Virtual screening identified fragments that could be fused into the core scaffold, exploiting additional binding interactions and thus improving potency. These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding. Despite these significant improvements no significant antibacterial activity was yet observed within this class.
authors.affiliation: Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: Peter.Doig@astrazeneca.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Doig
authors.affiliation: Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, MA 02451, United States.
authors.forename: Jacques
authors.initials: J
authors.lastname: Dumas
authors.affiliation: Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, MA 02451, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Kazmirski
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuroda
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Tomo-o
authors.initials: TO
authors.lastname: Sato
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Tohyama
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoi
authors.affiliation: Wakunaga Pharmaceutical Co. Ltd, Akitakata City, Hiroshima 739-1195, Japan.
authors.forename: Kazusa
authors.initials: K
authors.lastname: Wakamatsu
authors.affiliation: Infection Innovative Medicines, AstraZeneca R&D Boston, Waltham, MA 02451, United States.
authors.forename: Hongming
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006192:Haemophilus Infections / Q000188:drug therapy / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C573775:4-aminoquinazoline; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; C520333:GlmU protein, E coli; D009097:Multienzyme Complexes; D011799:Quinazolines
keywords: Aminoquinazoline; Cell wall biosynthesis; GlmU; N-Acetylglucosamine-1-phosphate; Uridyltransferase; Virtual screening