9PAQ
Crystal Structure of the Klebsiella pneumoniae LpxH/E2-1 Complex
This is a non-PDB format compatible entry.
Summary for 9PAQ
| Entry DOI | 10.2210/pdb9paq/pdb |
| Descriptor | UDP-2,3-diacylglucosamine hydrolase, N-(4-{2-[4-(3,5-dichlorophenyl)piperazin-1-yl]-2-oxoethyl}phenyl)-2-[(methanesulfonyl)(methyl)amino]benzamide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total) |
| Functional Keywords | lipid a, lpxh, gram-negative bacteria, antibiotic |
| Biological source | Klebsiella pneumoniae |
| Total number of polymer chains | 1 |
| Total formula weight | 30712.54 |
| Authors | |
| Primary citation | Zhang, G.,Cochrane, C.S.,Yang, B.,Zhao, J.,Jin, H.,Wu, S.,Zhou, P.,Xia, J. Structure-Based Discovery of a New LpxH-Targeted Chemotype with Activity against Klebsiella pneumoniae. J.Med.Chem., 69:6691-6705, 2026 Cited by PubMed Abstract: Gram-negative pathogens are difficult to treat because their outer membrane, enriched with lipid A-anchored lipopolysaccharide, serves as a protective barrier to many antibiotics. LpxH, an essential dimanganese hydrolase in lipid A biosynthesis, represents a promising antimicrobial target, but its distinct L-shaped binding pocket has limited inhibitor development, with only the sulfonylpiperazine chemotype reported to date. To broaden the chemical space, we developed a multistage virtual screening workflow combining HipHop-based pharmacophore modeling, ROCS-based query matching, and FRED docking. This pipeline identified , an acetylpiperazine-containing compound, as a moderate LpxH (LpxH) inhibitor. Substructure searching and optimization yielded compound , a potent inhibitor (IC: 0.17 μM) with moderate antibacterial activity (MIC: 5.3 μg/mL). The crystal structure of the LpxH-compound complex revealed its binding mode, validating virtual screening analysis. These studies establish acetylpiperazine derivatives as a new class of LpxH inhibitors and provide a foundation for future antibiotic development. PubMed: 41784176DOI: 10.1021/acs.jmedchem.5c02939 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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