Introduction: Quorum sensing (QS) is a well-known phenomenon which governs the inter communication in bacteria by the production of signaling molecules called “auto inducers”. Curbing of this “bacterial talk” is mainly preferred as a novel strategy to fight against growing antibiotic resistance worldwide by the use of Quorum Sensing Inhibitors (QSI).
Objective: The purpose of this study is to fight against the global problem of antibiotic resistance by identifying suitable quorum sensing inhibitors. The authors have attempted to identify food borne poly phenols as Quorum Sensing Inhibitors in C. violaceum using molecular docking based virtual screening. It also focuses on biological evaluations of possible quorum sensing inhibitors.
Methods: In the present work, the authors have performed virtual screening of Phenol explorer database containing 506 different food borne poly phenols against the CviR protein of C. violaceum. Polyphenolic classes were further ranked as per their binding affinities with CviR receptor also the pharmacokinetics and toxicity fitness scores of 25 best-docked ligands were analyzed by performing Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) studies. The top two compounds with the best docked scores were further investigated by calculating their interaction energies with key amino residues of CviR receptor on B3LYP/6-31+G(d):PM6 level along with their Harmonic Oscillator Model of Aromaticity(HOMA), Bird aromaticity indices and localized orbital locator Integrated Pi Over Plane(LOLIPOP) value of aromatic ring involved in forming hydrophobic interaction with the protein. The biological assays of the plant extract rich in the best docked polyphenols were evaluated using violace in inhibition assay.
Results: The study resulted with the identification of 25 phyto chemicals having higher scoring functions than endogenous ligand of C. violaceum. Among which 11 compounds were found to be devoid of any toxic implications as per observed values for Lipinski violations. The interaction energies of top two best docked compounds C410 and C439were found to be-20.65 kcal/mol and -4.39 kcal/mol respectively (EC410 = -20.65 kcal/mol and EC439= -4.39 kcal/mol). The docking and Density Functional Theory(DFT) studies predicted that ARG31, ASN142, ASP146, and ARG158 amino acids to be critically important residues involved in the QS inhibition activity. The stability of C410 and C439compoundsinside the active site of CviR was explained on the basis of HOMA, Bird aromaticity indices and LOLIPOP value. The anti-QS activity of these two compounds against C. violaceum was confirmed on the basis of Violace in inhibition assay.
Conclusion: Hence, the reported work sets another milestone in the identification of natural polyphenolic scaffolds as Quorum Sensing Inhibitors using computational insights and biological evaluations approaches.
Keywords: Quorum Sensing, Polyphenols, Density Functional Theory, C. violaceum, Violacein inhibition assay