Application of molecular docking and ONIOM methods for the description of interactions between anti-quorum sensing active (AHL) analogues and the Pseudomonas aeruginosa LasR binding site

Abstract

Molecular docking methods were applied to simulate the coupling of a set of nineteen acyl homoserine lactone analogs into the binding site of the transcriptional receptor LasR. The best pose of each ligand was explored and a qualitative analysis of the possible interactions present in the complex was performed. From the results of the protein-ligand complex analysis, it was found that residues Tyr-64 and Tyr-47 are involved in important interactions, which mainly determine the antagonistic activity of the AHL analogues considered for this study. The effect of different substituents on the aromatic ring, the common structure to all ligands, was also evaluated focusing on how the interaction with the two previously mentioned tyrosine residues was affected. Electrostatic potential map calculations based on the electron density and the van der Waals radii were performed on all ligands to graphically aid in the explanation of the variation of charge density on their structures when the substituent on the aromatic ring is changed through the elements of the halogen group series. A quantitative approach was also considered and for that purpose the ONIOM method was performed to estimate the energy change in the different ligand-receptor complex regions. Those energy values were tested for their relationship with the corresponding IC50 in order to establish if there is any correlation between energy changes in the selected regions and the biological activity. The results obtained using the two approaches may contribute to the field of quorum sensing active molecules; the docking analysis revealed the role of some binding site residues involved in the formation of a halogen bridge with ligands. These interactions have been demonstrated to be responsible for the interruption of the signal propagation needed for the quorum sensing circuit. Using the other approach, the structure-activity relationship (SAR) analysis, it was possible to establish which structural characteristics and chemical requirements are necessary to classify a compound as a possible agonist or antagonist against the LasR binding site.

3-Aminooxazolidinone AHL analogs as hydrolytically-stable quorum sensingagonists in Gram-negative bacteria

“…Recently Blackwell also revealed that the interactions between a ligand and Tyr56 and Ser129 in LasR are also important in determining whether a ligand acts as an antagonist or agonist since these residues bond to the carbonyl of the 3-oxo-C12-HSL ligand to position the lactone head group towards Tyr 60, which is a key residue. 45,47 Docking experiments [48][49][50] revealed that the docked poses of 3-oxo-C12-HSL and of the 3-aminooxazolidinone analog (1) are similar, with the exception of the orientation of the 3-oxo group (see Fig. 4).…”

Mutational Analysis of the Quorum-Sensing Receptor LasR Reveals Interactions that Govern Activation and Inhibition by Nonlactone Ligands

“…These dramatic activity switches are seemingly caused by relatively subtle changes in ligand structure; however, the molecular bases for these flips in activity are unclear. In fact, there is virtually no information about the molecular mechanisms by which any non-native AHL analog modulates LuxR-type receptors (Ahumedo et al, 2014; Chen et al, 2011). Elucidating the causes of receptor activation versus inhibition by AHL analogs would not only improve our understanding of the molecular foundations of AHL-based QS, but would also augment our ability to design more potent molecular probes to modulate this signaling pathway.…”

Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri-Quorum Sensing Modulators

“…Overall, an additional hydrogen bond with the Tyr70 residue is found for most carbamate/thiocarbamate analogues. The Tyr70 residue, which is a conserved residue in the LuxR proteins family (equivalent to Tyr64 in LasR [38]) is confirmed as particularly important for interactions with AHLs analogues. For nitro compounds 7 and 11, two additional hydrogen bonds involving the nitro group and the Lys178 residue have been identified ( Figure 3B).…”