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

Wang J, Zhou X, Liu S, Li G, Zhang B, Deng X, Niu X - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.

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.

Show MeSH

Related in: MedlinePlus

The chemical structures of the LLO inhibitors used for molecular simulation and binding free energy calculations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4352855&req=5

f1: The chemical structures of the LLO inhibitors used for molecular simulation and binding free energy calculations.

Mentions: LLO has been proposed to be a promising target for the development of antilisteriosis drugs. Screening for inhibitors of LLO would facilitate the process of developing anti-LLO drugs for the treatment of infections. In the present study, we focused on five natural compounds, Myr, Mor, Bac, Chr and Nar (Fig. 1), identified in a screen of over 100 natural compounds for antagonism of the hemolytic activity of LLO. These five inhibitors belong to the flavonoid family and share structural similarities, but have with different inhibitory activities (Fig. 2a). Under our experimental conditions, the concentrations required for 50% inhibition (IC50) were 0.46, 0.87, 0.92, 13.65 and 186.57 μg/ml for Myr, Mor, Bac, Chr and Nar, respectively (Fig. 2a). Myr displayed the strongest inhibitory action among these five natural compounds (Fig. 2a).


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

Wang J, Zhou X, Liu S, Li G, Zhang B, Deng X, Niu X - Sci Rep (2015)

The chemical structures of the LLO inhibitors used for molecular simulation and binding free energy calculations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352855&req=5

f1: The chemical structures of the LLO inhibitors used for molecular simulation and binding free energy calculations.
Mentions: LLO has been proposed to be a promising target for the development of antilisteriosis drugs. Screening for inhibitors of LLO would facilitate the process of developing anti-LLO drugs for the treatment of infections. In the present study, we focused on five natural compounds, Myr, Mor, Bac, Chr and Nar (Fig. 1), identified in a screen of over 100 natural compounds for antagonism of the hemolytic activity of LLO. These five inhibitors belong to the flavonoid family and share structural similarities, but have with different inhibitory activities (Fig. 2a). Under our experimental conditions, the concentrations required for 50% inhibition (IC50) were 0.46, 0.87, 0.92, 13.65 and 186.57 μg/ml for Myr, Mor, Bac, Chr and Nar, respectively (Fig. 2a). Myr displayed the strongest inhibitory action among these five natural compounds (Fig. 2a).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.

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.

Show MeSH
Related in: MedlinePlus