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Pseudomonas aeruginosainfections are a leading cause of death in patients suffering from respiratory diseases. The multidrug-resistant nature of Pseudomonasis potentiated by a process known as quorum sensing. The aim of this study was to reveal new inhibitors of a well-validated but quite unexplored target, enoyl-ACP reductase, which contributes acyl chain lengths of N-acyl homoserine lactones that are major signaling molecules in gram-negative bacteria. In the present study, the crystal structure of FabI (PDB, ID 4NR0) was used for the structure-based identification of quorum sensing inhibitors of Pseudomonas aeruginosa. Active site residues of FabI were identified from the complex of FabI with triclosan and these active site residues were further used to screen for potential inhibitors from natural database. Three-dimensional structures of the 75 natural compounds were retrieved from the ZINC database and screened using PyRX software against FabI. Thirty-eight molecules from the initial screening were sorted on the basis of binding energy, using the known inhibitor triclosan as a standard. These molecules were subjected to various secondary filters, such as Lipinski’s Rule of Five, ADME, and toxicity. Finally, eight lead-like molecules were obtained after their evaluation for drug-like characteristics. The present study will open a new window for designing QS inhibitors against P. aeruginosa.