Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling

Scientific Reports
Jianfeng WangXiaodi Niu

Abstract

Increasing bacterial resistance to available antibiotics makes the discovery of novel efficacious antibacterial agents a priority. A previous report showed that listeriolysin O (LLO) is a critical virulence factor and suggested that it is a target for developing anti-virulence drugs against Listeria monocytogenes infections. In this study, we report the discovery of LLO natural compound inhibitors with differential activity by using hemolysis assay. The mechanism of action of the inhibitors was consistent with that of fisetin, a natural flavonoid without antimicrobial activity, which we showed in our previous report via molecular simulation. Furthermore, a substantial increase in anti-hemolytic activity was observed when the single bond (C1-C2) was replaced by a double bond (C1-C2) in the inhibitor molecule. This change was based on the decomposition of the ligand-residue interaction, which indicated that the double bond (C1-C2) in the inhibitors was required for their inhibition of LLO. The current MD simulation work provides insights into the mechanism by which the compounds inhibit LLO at the atomic level and will be useful for the development of new, selective LLO inhibitors.

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Citations

Jul 21, 2016·Chemical Reviews·Laura Nunes SilvaDanielle Silva Trentin
Apr 15, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bingrun LiuDacheng Wang
Oct 20, 2018·Journal of Cellular and Molecular Medicine·Jianfeng WangXuming Deng
Mar 2, 2018·Frontiers in Microbiology·Jianfeng WangXuming Deng
Aug 24, 2019·Microbiology Spectrum·Jörgen Johansson, Nancy E Freitag
Jun 3, 2021·Pharmaceutics·Giuliana DonadioFabrizio Dal Piaz

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Methods Mentioned

BETA
fluorescence
fluorescence spectroscopy
PCR
X-ray

Software Mentioned

Amber10
Gaussian 03
antechamber
AutoDock4
Gromacs
Amber
AM1

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Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

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