4KPZ

Hin GlmU bound to a small molecule fragment

Summary for 4KPZ

• Entry DOI: 10.2210/pdb4kpz/pdb
• Related: 4KNR 4KNX 4KPX 4KQL
• Descriptor: Bifunctional protein GlmU, 1-(3-nitrophenyl)dihydropyrimidine-2,4(1H,3H)-dione, SULFATE ION, ... (6 entities in total)
• Functional Keywords: beta helix, cell wall biosynthesis, transferase
• Biological source: Haemophilus influenzae
• Cellular location: Cytoplasm : P43889
• Total number of polymer chains: 1
• Total formula weight: 50594.70

Authors

Doig, P.,Kazmirski, S.L.,Boriack-Sjodin, P.A. (deposition date: 2013-05-14, release date: 2014-10-15, Last modification date: 2024-02-28)

Primary citation

Doig, P.,Boriack-Sjodin, P.A.,Dumas, J.,Hu, J.,Itoh, K.,Johnson, K.,Kazmirski, S.,Kinoshita, T.,Kuroda, S.,Sato, T.O.,Sugimoto, K.,Tohyama, K.,Aoi, H.,Wakamatsu, K.,Wang, H.
Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping.
Bioorg.Med.Chem., 22:6256-6269, 2014

PubMed 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.

PubMed: 25262942
DOI: 10.1016/j.bmc.2014.08.017

Experimental method

X-RAY DIFFRACTION (2.09 Å)