Macromolecular Structural Biology Lab, Department of Biotechnology, Indian Institute of Technology, Hyderabad, Telangana, India.
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur, Maharashtra, India.
J Biomol Struct Dyn. 2024 Oct;42(16):8427-8440. doi: 10.1080/07391102.2023.2246568. Epub 2023 Aug 11.
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. 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.
抗生素耐药性已成为全球紧迫的健康危机，由于多药耐药性的出现，细菌感染越来越难以治疗。本研究旨在使用先进的计算工具，鉴定与大肠杆菌中两种关键多药外排泵（AcrB 和 EmrD）相互作用的潜在查尔酮分子。对包含 100 种查尔酮化合物的配体文库进行了 ADMET（吸收、分布、代谢、排泄和毒性）、药物相似性预测、分子对接和分子动力学模拟分析，以针对 AcrB（PDB：4DX5）和 EmrD（PDB：2GFP）。结果表明，Elastichalcone A（PubChem CID 102103730）对 AcrB 表现出显著的结合亲和力-9.9 kcal/mol，而 4'-甲氧基-4-羟基查尔酮（PubChem CID 5927890）对 EmrD 表现出-9.8 kcal/mol 的结合亲和力。这两种配体都符合药物相似性规则，具有良好的药代动力学特性。AcrB-Elastichalcone A 复合物的分子动力学模拟在 100 ns 以上保持稳定，均方根偏差和均方根波动最小。筛选的配体文库表现出良好的药物相似性和药代动力学特性。此外，MM/PB(GB)SA 计算表明模拟蛋白-配体复合物具有紧密的结合和热力学稳定性。总的来说，这项研究强调了查尔酮作为针对多药外排泵的有前途候选药物的潜力，为克服抗生素耐药性提供了一种潜在策略。进一步探索和优化这些化合物可能会导致开发针对多药耐药细菌感染的有效治疗方法。由 Ramaswamy H. Sarma 交流。
