4kpz | pdb_00004kpz
Hin GlmU bound to a small molecule fragment
Structural highlights
FunctionGLMU_HAEIN Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.[1] Publication Abstract from PubMedAn 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. Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping.,Doig P, Boriack-Sjodin PA, Dumas J, Hu J, Itoh K, Johnson K, Kazmirski S, Kinoshita T, Kuroda S, Sato TO, Sugimoto K, Tohyama K, Aoi H, Wakamatsu K, Wang H Bioorg Med Chem. 2014 Sep 16. pii: S0968-0896(14)00604-X. doi:, 10.1016/j.bmc.2014.08.017. PMID:25262942[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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