The present work combines molecular docking calculations, 3D-QSAR, molecular 
dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) 
in a set of 28 structural analogues of acyl homoserine lactones with Quorum 
Sensing antagonist activity. The aim of this work is to understand how ligand 
binds and is affected by the molecular microenvironment in the active site of 
the LasR receptor for pseudomonas aeruginosa. We also study the stability of the 
interaction to find key structural characteristics that explain the antagonist 
activities of this set of ligands. This information is relevant for the rational 
modification or design of molecules and their identification as powerful LasR 
modulators. The analysis of molecular docking simulations shows that the 28 
analogues have a similar binding mode compared to the native ligand. The 
carbonyl groups belonging to the lactone ring and the amide group of the acyl 
chain are oriented towards the amino acids forming hydrogen bond like 
interactions. The difference in antagonist activity is due to location and 
orientation of the LasR side chains within the hydrophobic pocket in its binding 
site. Additionally, we carried out molecular dynamics simulations to understand 
the conformational changes in the ligand-receptor interaction and the stability 
of each complex. Results show a direct relationship among the interaction 
energies of the ligands and the activities as an antagonist of the LasR 
receptor.