VIRTUAL SCREENING: IDENTIFICATION OF COMPOUNDS WITH POSSIBLE QUORUM SENSING AGONISTIC ACTIVITY IN Pseudomonas aeruginosa

Abstract

Background: Quorum sensing (QS) is a cell density dependent mechanism that allows bacteria to regulate the expression of specific genes in response to changes in their population density, thus controlling their activities in order to produce a response as a unit multicellular. These responses include production of virulence factors, formation of biofilm, bioluminescence, sporulation, among other behavior. Objectives: The objective of this work was to obtain pharmacophore models able to filter and identify molecules with possible agonist activity of uorum sensing and to find possible candidates based on calculations of molecular docking. Methods: The structure of the receptor was taken from the Protein Data Bank (PDB). The program AutoDock 4.2 was used to perform docking calculations. The 3D structure of the ligand TP1 was extracted from the complex co-crystallized identified with the code PDB 3IX3. The geometries of ligands were optimized using the PM3 semiempirical method. Results: Two pharmacophoric models were designed, the first one was made using the most active compound (TP-1), highlighting the most important chemical characteristics for molecular recognition. The second model was based on the alignment of three of the most active ligands (TP-1, TP-3 and TP-4). These models were used as a filter in a screening on a database of conformations of several compounds with possible agonist activity of the main circuit of QS present in Pseudomonas aeruginosa. The pharmacophoric model based on alignment of the most active compounds showed greater capacity to select or identify compounds exhibiting significant structural and chemical characteristics to be considered possible hit. With this model, 22 compounds were identified. These compounds were subjected to a series of calculations of docking. The outcomes of the docking were used to identify interactions making a SAR analysis and were used as support to understand how chemically distinct compounds can be accommodated by a highly selective receptor, and provide the framework for the development of novel quorum-sensing regulators, utilizing the 2-benzamido(methyl) phenyl benzoate scaffold and to assess the possibility of synthetic routes, considering the structural similarity presenting between these compounds, generating in this way an alternative to find new compounds with modulating activity QS. These two strategies were used to select a list of potential modulators of quorum sensing or new pharmacophoric candidates.

Biofilm and Quorum Sensing in Helicobacter pylori

“…To date, few H. pylori QSIs were described, whether synthetic or produced by living organisms, such as plants, animals, and bacteria [80][81][82]. Flavonoids, i.e., naringenin, quercetin, myricetin, baicalein, catechin, flavone, and turmeric, exhibited promising antibiofilm and antiadhesive properties against H. pylori [83-88] (Table 2).…”

Energy-Optimized Pharmacophore Coupled Virtual Screening in the Discovery of Quorum Sensing Inhibitors of LasR Protein of <em>Pseudomonas aeruginosa</em>

“…The generation of multiple hypotheses is required to identify the best pharmacophore model that is able to render a potential outcome [78] . Also, molecules shared structure similarity also possess similar activity [79] . Therefore, two structurally similar compounds, i.e., CID9795780 (3-oxo-N-(2-oxooxolan-3yl)undecanamide) and CID9882952 (4,4-Difluoro-3-oxo-N-(2-oxooxolan-3-yl)decanamide), were retrieved using the native ligand.…”