Identification of the Inhibitory Compounds for Metallo-β-lactamases and Structural Analysis of the Binding Modes
| Autor: | Michiyoshi Nukaga, Tyuji Hoshino, Akiko Takaya, Taichi Kamo, Keiichi Kuroda, Tomoki Yoneda, Usaki Hayashi, Shota Kondo, Satoshi Fudo |
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| Přispěvatelé: | Department of Bacteriology and Immunology, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE |
| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
enzyme inhibitor Molecular Dynamics Simulation Inhibitory postsynaptic potential 01 natural sciences beta-Lactamases Metallo β lactamase 03 medical and health sciences chemistry.chemical_compound Molecular dynamics RIBONUCLEASE-H DOMAIN Drug Discovery metallo-beta-lactamase Humans CRYSTAL-STRUCTURE antimicrobial resistance structural analysis Thiazole chemistry.chemical_classification 0303 health sciences Binding Sites Molecular Structure biology 010405 organic chemistry 030306 microbiology General Chemistry General Medicine In vitro ENDONUCLEASE 0104 chemical sciences Enzyme chemistry Enzyme inhibitor biology.protein 1182 Biochemistry cell and molecular biology New delhi beta-Lactamase Inhibitors thiazole COMPOUNDS TARGETING TRKB |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 69:1179-1183 |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.c21-00611 |
| Popis: | Metallo-beta-lactamases (MBLs) are significant threats to humans because they deteriorate many kinds of beta-lactam antibiotics and are key enzymes responsible for multi-drug resistance of bacterial pathogens. As a result of in vitro screening, two compounds were identified as potent inhibitors of two kinds of MBLs: imipenemase (IMP-I) and New Delhi metallo-beta-lactamase (NDM-1). The binding structure of one of the identified compounds was clarified by an X-ray crystal analysis in complex with IMP-1, in which two possible binding poses were observed. Molecular dynamics (MD) simulations were performed by building two calculation models from the respective binding poses. The compound was stably bound to the catalytic site during the simulation in one pose. The binding model between NDM-1 and the compound was constructed for MD simulation. Calculation results for NDM-1 were similar to those of IMP-1. The simulation suggested that the binding of the identified inhibitory compound was also durable in the catalytic site of NDM-1. The compound will be a sound basis for the development of the inhibitors for MBLs. |
| Databáze: | OpenAIRE |
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