10RY

Crystal structure of compound 8t bound to PaLpxC

This is a non-PDB format compatible entry.

Summary for 10RY

• Entry DOI: 10.2210/pdb10ry/pdb
• Descriptor: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, 1-{(2S)-3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)-2-[4-({4-[(morpholin-4-yl)methyl]phenyl}ethynyl)phenyl]propyl}azetidine-3-carbonitrile, ... (5 entities in total)
• Functional Keywords: inhibitor complex, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 34046.99

Authors

Martin, D.P. (deposition date: 2026-02-04, release date: 2026-08-19, Last modification date: 2026-08-26)

Primary citation

Martin, D.P.,Teng, M.,Nammalwar, B.,Perez, C.,Li, X.,Munguia, J.,Taganov, K.,Fan, J.,Agarwalla, S.,Lonergan, D.,Tomaras, A.P.,Zimmerman, Z.,Puerta, D.T.
Discovery and Optimization of Novel Nonhydroxamate LpxC Inhibitors for the Treatment of Multidrug-Resistant Gram-Negative Infections.
J.Med.Chem., 69:18692-18704, 2026

PubMed Abstract: This report summarizes the discovery and optimization of a novel series of nonhydroxamate inhibitors targeting LpxC, a Zn2+-dependent hydrolase that is essential for the survival of Gram-negative bacteria. Beginning with a 5-hydroxypyrimidin-4-one metal-binding pharmacophore, structure-based approaches were utilized to generate a series of potent inhibitors that exhibited activity against a wide variety of Enterobacterales, including both susceptible and multidrug-resistant pathogens, and efficacy in murine thigh infection models. These novel compounds were evaluated in a rat model of cardiovascular toxicity to demonstrate the safety of the scaffold relative to another LpxC inhibitor that proved unsuccessful in Phase I clinical trials. A variety of inhibitors with potent in vivo efficacy and no hemodynamic effects were identified, which constituted an initial suite of potential development candidates.

PubMed: 42593942
DOI: 10.1021/acs.jmedchem.6c01036

Experimental method

X-RAY DIFFRACTION (1.902 Å)