Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR of<i>Pseudomonas aeruginosa</i>: Insights from molecular docking and dynamics simulations

Hunanyan

et al. 2017

Preprint

Self Cite

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 93%

“…Previously modeled LasR monomer structure was used for study [10]. The 2D and 3D structure of quercetin were obtained from PubChem [18] and they are shown in Figure 1.…”

Section: Lasr and Quercetin Modelsmentioning

confidence: 99%

Section: Molecular Dynamics Simulations Of Lasr-quercetin Systemsmentioning

confidence: 99%

“…The whole methodology is based on our previous research [10] and is presented as a flowchart for a better comprehension:…”

Section: Entire Flowchartmentioning

confidence: 99%

See 3 more Smart Citations

Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing

Hunanyan

et al. 2017

Preprint

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Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR

2018

Preprint

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Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.

Identification of flavone and its derivatives as potential inhibitors of transcriptional regulator LasR of Pseudomonasaeruginosausing virtual screening

Abelyan

2019

Preprint

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Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using multiple docking programs for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro / in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.