Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping

• Published in: Bioorganic & medicinal chemistry 2014-11, Vol.22 (21), p.6256-6269
• Main Authors: Doig, Peter, Boriack-Sjodin, P. Ann, Dumas, Jacques, Hu, Jun, Itoh, Kenji, Johnson, Kenneth, Kazmirski, Steven, Kinoshita, Tomohiko, Kuroda, Satoru, Sato, Tomo-o, Sugimoto, Kaori, Tohyama, Katsumi, Aoi, Hiroshi, Wakamatsu, Kazusa, Wang, Hongming
• Format: Article
• Language: English
• Subjects: Aminoquinazoline; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteria; Cell Wall - drug effects; Cell Wall - enzymology; Cell wall biosynthesis; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - metabolism; GlmU; Haemophilus Infections - drug therapy; Haemophilus Infections - microbiology; Haemophilus influenzae - drug effects; Haemophilus influenzae - enzymology; Humans; Molecular Docking Simulation; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; N-Acetylglucosamine-1-phosphate; Quinazolines - chemistry; Quinazolines - pharmacology; Uridyltransferase; Virtual screening
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.08.017

[Display omitted] 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.