Exploring α, β-unsaturated carbonyl compounds against bacterial efflux pumps via computational approach.

Antibiotic resistance has become a pressing global health crisis, with bacterial infections increasingly difficult to treat due to the emergence of multidrug resistance. This study aims to identify potential chalcone molecules that interact with two key multidrug efflux pumps, AcrB and EmrD, of Escherichia coli, using advanced computational tools. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity), drug-likeness prediction, molecular docking, and molecular dynamics simulation analyses were conducted on a ligand library comprising 100 chalcone compounds against AcrB (PDB: 4DX5) and EmrD (PDB: 2GFP). The results demonstrated that Elastichalcone A (PubChem CID 102103730) exhibited a remarkable binding affinity of -9.9 kcal/mol against AcrB, while 4'-methoxy-4-hydroxychalcone (PubChem CID 5927890) displayed a binding affinity of -9.8 kcal/mol against EmrD. Both ligands satisfied drug-likeness rules and possessed favorable pharmacokinetic profiles. Molecular dynamics simulation of the AcrB-Elastichalcone A complex remained stable over 100 ns, with minimal fluctuations in root-mean-square deviation and root-mean-square fluctuation. The screened ligand library demonstrated good drug-likeness and pharmacokinetic properties. Moreover, the MM/PB(GB)SA calculation indicated the tight binding and thermodynamic stability of the simulated protein-ligand complexes. Overall, this study highlights the potential of chalcones as promising candidates for targeting multidrug efflux pumps, offering a potential strategy to overcome antibiotic resistance. Further exploration and optimization of these compounds may lead to the development of effective therapeutics against multidrug-resistant bacterial infections.Communicated by Ramaswamy H. Sarma.