Discovery of AcrAB-TolC pump inhibitors: Virtual screening and molecular dynamics simulation approach

AcrAB-TolC tripartite efflux pump, which belongs to the RND superfamily, is a main multi-drug efflux system of Escherichia coli (E. coli) because of the broad resistance on various antibiotics. With the discovering of efflux pump inhibitors (EPIs), a combination between these and antibiotics is one of the most promising therapies. Therefore, building a virtual screening model with prediction capacities for the efflux pump inhibitory activities of candidates from DrugBank and ZINC15 dataset, is one of the key goals of this project. Based on the database of 170 diverse chemical structures collected from 28 research journals, two 2D-QSAR models and a 3D-pharmacophore model have been performed. On the AcrB protein (PDB 4DX7), two binding sites have been discovered that match to the hydrophobic trap in the distal pocket and the switch loop in the proximal pocket. After virtual screening processes, twenty candidate AcrAB-TolC inhibitors have been subjected to molecular dynamics simulations, binding free energy calculations and ADMET predictions. The results indicate that three compounds namely DB09233, DB02581, and DB15224 are potential inhibitors with ΔG_bind of -42.30 ± 4.58, -40.76 ± 7.30 and -31.06 ± 7.63 kcal.mol^-1, respectively.Communicated by Ramaswamy H. Sarma.