Fluorescent Trimethylated Naphthyridine Derivative with an Aminoalkyl Side Chain as the Tightest Non-aminoglycoside Ligand for the Bacterial A-site RNA
| Autor: | Seiichi Nishizawa, Masafumi Rokugawa, Yusuke Sato, Shô Itô, Hiroki Sugawara, Sayaka Yajima, Norio Teramae |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Stereochemistry Ligands 010402 general chemistry medicine.disease_cause 01 natural sciences Catalysis Structure-Activity Relationship Drug Resistance Bacterial Escherichia coli Side chain medicine Structure–activity relationship Naphthyridines Binding site Fluorescent Dyes Binding Sites Molecular Structure 010405 organic chemistry Chemistry Ligand Organic Chemistry Aminoglycoside RNA General Chemistry Anti-Bacterial Agents 0104 chemical sciences RNA Bacterial A-site Aminoglycosides Nucleic Acid Conformation Thermodynamics |
| Zdroj: | Chemistry - A European Journal. 24:13862-13870 |
| ISSN: | 0947-6539 |
| Popis: | The bacterial ribosomal decoding region of the aminoacyl-tRNA site (A-site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well-characterized A-site binding ligands, high off-target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non-aminoglycoside A-site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A-site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A-site (Kd =0.44 μm; pH 7.0, I=0.06 m, 5 °C). Significantly, this ligand shows the tightest binding reported to date among non-aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND-C2 -NH2 for high affinity to the A-site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A-site interactions. |
| Databáze: | OpenAIRE |
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