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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.

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The interactions between inhibitors and LLO predicted by molecular modeling.
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f3: The interactions between inhibitors and LLO predicted by molecular modeling.

Mentions: An overlay of the five modeling structures revealed that Myr, Mor, Bac, Chr and Nar bound LLO with the same binding mode (Fig. 3). Given the conservation of binding interactions between LLO and the shared components in Myr, Mor, Bac, Chr and Nar, we subsequently focused our discussion on the structure of the LLO-Myr complex, which has the highest activity. Information from the modeled structure of LLO-Myr derived from the docking results was used for the 200-ns molecular dynamics simulation, based on which the preferential mechanism of binding between Myr and LLO was established. These analyses revealed that hydrogen bonds and electrostatic interactions were involved in the formation of the LLO-Myr complex, in which two binding cavities, Loop 2 (L2) and the Loop 3 (L3) of the toxin, made direct contact with the Myr ligand (Fig. 3). Our modeling also indicated that the 4H-chromen-4-one moiety of the Myr could form strong interactions with the side chains of residues Tyr427, Val428, Gln430 and Phe431 in the L2 region. In addition, Myr is proximal to the residues, Phe464, Thr465, Ser466, Ser467 and Ile468 (L3 region), which suggests a strong stacking interaction between these residues and Myr. Due to the binding of inhibitors in the cavity of L2 and L3, the fluctuation of L2 was restricted, which led to an increase in the distance between L2 and L1. Such an increase made LLO less optimal for engaging CHO and this lower affinity for CHO consequently lowered its lytic activity. This mechanism is consistent with fisetin, a natural flavonoid without antimicrobial activity, which was identified in our previous report13.


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 interactions between inhibitors and LLO predicted by molecular modeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: The interactions between inhibitors and LLO predicted by molecular modeling.
Mentions: An overlay of the five modeling structures revealed that Myr, Mor, Bac, Chr and Nar bound LLO with the same binding mode (Fig. 3). Given the conservation of binding interactions between LLO and the shared components in Myr, Mor, Bac, Chr and Nar, we subsequently focused our discussion on the structure of the LLO-Myr complex, which has the highest activity. Information from the modeled structure of LLO-Myr derived from the docking results was used for the 200-ns molecular dynamics simulation, based on which the preferential mechanism of binding between Myr and LLO was established. These analyses revealed that hydrogen bonds and electrostatic interactions were involved in the formation of the LLO-Myr complex, in which two binding cavities, Loop 2 (L2) and the Loop 3 (L3) of the toxin, made direct contact with the Myr ligand (Fig. 3). Our modeling also indicated that the 4H-chromen-4-one moiety of the Myr could form strong interactions with the side chains of residues Tyr427, Val428, Gln430 and Phe431 in the L2 region. In addition, Myr is proximal to the residues, Phe464, Thr465, Ser466, Ser467 and Ile468 (L3 region), which suggests a strong stacking interaction between these residues and Myr. Due to the binding of inhibitors in the cavity of L2 and L3, the fluctuation of L2 was restricted, which led to an increase in the distance between L2 and L1. Such an increase made LLO less optimal for engaging CHO and this lower affinity for CHO consequently lowered its lytic activity. This mechanism is consistent with fisetin, a natural flavonoid without antimicrobial activity, which was identified in our previous report13.

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