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Molecular Docking, Molecular Dynamics Simulations, Computational Screening to Design Quorum Sensing Inhibitors Targeting LuxP of Vibrio harveyi and Its Biological Evaluation

Abstract

Quorum sensing (QS) plays an important role in the biofilm formation, production of virulence factors and stress responses in Vibrio harveyi. Therefore, interrupting QS is a possible approach to modulate bacterial behavior. In the present study, three docking protocols, such as Rigid Receptor Docking (RRD), Induced Fit Docking (IFD), and Quantum Polarized Ligand Docking (QPLD) were used to elucidate the binding mode of boronic acid derivatives into the binding pocket of LuxP protein in V. harveyi. Among the three docking protocols, IFD accurately predicted the correct binding mode of the studied inhibitors. Molecular dynamics (MD) simulations of the protein-ligand complexes indicates that the inter-molecular hydrogen bonds formed between the protein and ligand complex remains stable during the simulation time. Pharmacophore and shape-based virtual screening were performed to find selective and potent compounds from ChemBridge database. Five hit compounds were selected and subjected to IFD and MD simulations to validate the binding mode. In addition, enrichment calculation was performed to discriminate and separate active compounds from the inactive compounds. Based on the computational studies, the potent Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid-2,6-dimethylpyridine 1-oxide (ChemBridge_5144368) was selected for in vitro assays. The compound exhibited dose dependent inhibition in bioluminescence and also inhibits biofilm formation in V. harveyi to the level of 64.25 %. The result from the study suggests that ChemBridge_5144368 could serve as an anti-quorum sensing molecule for V. harveyi.

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Correspondence to Pappu Srinivasan.

Electronic supplementary material

Supplementary Fig. 1
figure13

The RMSD of C-α atom from the starting structure as the function of the simulation time (GIF 215 kb)

Supplementary Fig. 2
figure14

RMSF of C-α atom in coordinates of each residue averaged over the duration of the MD simulation (GIF 173 kb)

Supplementary Fig. 3
figure15

Hydrogen bonding number versus simulation time (GIF 25 kb)

Supplementary Fig. 4
figure16

Effect of ChemBridge_5144368 on biofilm formation of V. harveyi (GIF 10 kb)

High resolution image (TIFF 10443 kb)

High resolution image (TIFF 8975 kb)

High resolution image (TIFF 1484 kb)

High resolution image (TIFF 1224 kb)

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Rajamanikandan, S., Jeyakanthan, J. & Srinivasan, P. Molecular Docking, Molecular Dynamics Simulations, Computational Screening to Design Quorum Sensing Inhibitors Targeting LuxP of Vibrio harveyi and Its Biological Evaluation. Appl Biochem Biotechnol 181, 192–218 (2017). https://doi.org/10.1007/s12010-016-2207-4

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Keywords

  • Quorum sensing
  • Boronic acid derivatives
  • Molecular docking
  • Molecular dynamics simulations
  • In vitro assays