The Alpha-Naphthoflavone as a Novel Scaffold for the Design of Potential Inhibitors of APH (3')-IIIa of Enterococcus Faecalis: An In-Silico Study

Abstract:

Nosocomial infections remain a constant threat worldwide mainly due to antibiotic resistance of species such as Enterococcus faecalis. Among the main classes of antibiotics used against this bacterium are the aminoglycosides, but many resistance mechanisms compromise their effectiveness. The action of aminoglycoside modifying enzymes represents one of the most studied mechanisms, mainly because it is one of the most representative in enterococci. Based on this problem, this work used 462 flavones from the ChemSpace database of small molecules to find potential aminoglycoside adjuvants, testing the affinity of these molecules with the nucleotide-binding pocket of aminoglycoside phosphotransferase type IIIa of E. faecalis (Ef APH (3')-IIIa). The best binding energy in the molecular docking-based virtual screening was reached by the alpha-naphthoflavone CSSB00000067355 (2-phenyl-4H-benzo [h] chromen-4-one). After structural optimization, a novel derivative designed from this naphthoflavone exhibited higher free binding energy, better stability in molecular dynamics analyses and a superior pharmacokinetic and toxicological profile. These results together reveal for the first time an alpha-naphthoflavone as a scaffold to the design of promising aminoglycoside adjuvants by interacting with nucleotide-binding pocket of Ef APH (3')-IIIa.

Año de publicación:

2022

Keywords:

Fuente:

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