8Z5L

Crystal structure of metallo-beta-lactamse, IMP-1, complexed with a quinolinone-based inhibitor

This is a non-PDB format compatible entry.

Replaces:  8Y0S

Summary for 8Z5L

• Entry DOI: 10.2210/pdb8z5l/pdb
• Descriptor: Metallo-beta-lactamase type 2, ZINC ION, 3-[2-azanyl-5-[2-cyclohexylethyl-[3-(4-methylphenoxy)propyl]amino]phenyl]propanoic acid, ... (4 entities in total)
• Functional Keywords: beta-lactamase inhibitor, antibiotic, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Serratia marcescens
• Total number of polymer chains: 4
• Total formula weight: 104403.47

Authors

Kamo, T.,Kuroda, K.,Nimura, S.,Guo, Y.,Kondo, S.,Nukaga, M.,Hoshino, T. (deposition date: 2024-04-18, release date: 2024-05-08, Last modification date: 2024-06-05)

Primary citation

Kamo, T.,Kuroda, K.,Nimura, S.,Guo, Y.,Kondo, S.,Nukaga, M.,Hoshino, T.
Development of Inhibitory Compounds for Metallo-beta-lactamase through Computational Design and Crystallographic Analysis.
Biochemistry, 63:1278-1286, 2024

PubMed Abstract: Metallo-β-lactamases (MBL) deactivate β-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring. In the first step, the thiazole ring was replaced with a tertiary amine to avoid the planar structure. In the second step, we virtually modified the compound by keeping the quinolinone backbone. Every modified compound was bound to a kind of MBL, imipenemase-1 (IMP-1), and the binding pose was optimized by a molecular mechanics calculation. The binding scores were evaluated for the respective optimized binding poses. Given the predicted binding poses and calculated binding scores, candidate compounds were determined for organic syntheses. The inhibitory activities of the synthesized compounds were measured by an in vitro assay for two kinds of MBLs, IMP-1 and New Delhi metallo-β-lactamase (NDM-1). A quinolinone connected with an amine bound with methyl-phenyl-ether-propyl and cyclohexyl-ethyl showed a 50% inhibitory concentration of 4.8 μM. An X-ray crystal analysis clarified the binding structure of a synthesized compound to IMP-1. The δ-lactam ring of quinolinone was hydrolyzed, and the generated carboxyl group was coordinated with zinc ions. The findings on the chemical structure and binding pose are expected to be a base for developing MBL inhibitors.

PubMed: 38690676
DOI: 10.1021/acs.biochem.4c00069

Experimental method

X-RAY DIFFRACTION (2.65 Å)