Abstract: Drug resistances in Gram-negative bacteria arise through several mechanisms including that of an over-expression of the multidrug transporter AcrB and its homologues. This research works sought to use computational methods to understand structure and functional relationship using the binding energies and structural similarity of the lowest binding molecules. A series of 479 molecules including alkaloids, flavinoids, cyclic imides, lactams, lactones, NSAIDS, sulfanilamides, and known pharmaceuticals were bound to 10 AcrB crystal structures (1IWG, 1OY6, 1OY8, 1OY9, 1OYD, 2W1B, 2RDD, 2J8S, 2HRT, 2DRD). Computational results matched found a group of current pharmaceuticals maintaining the lowest energy overall. Similarity searches of the lowest binding molecules were conducted to determine important structural motifs. This research allows a better understanding of drug interaction towards the blockade of Gram-negative resistances.