School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India.
Department of Chemical Technology, University of Calcutta, Kolkata, India.
J Biomol Struct Dyn. 2021 Feb;39(3):923-942. doi: 10.1080/07391102.2020.1720819. Epub 2020 Feb 12.
Drug resistance is an unsolved and major concern in the bacterial infection. Continuous development of drug-resistance to the antibiotics exponentially rises the danger of bacterial infections. Chemical components from the plants are becoming a major resource of potentially effective therapeutic chemical agents for the wide range of diseases including bacterial infections. In the current study, pharmacoinformatics methodologies were implemented on more than two hundred known phytochemicals to find promising beta-lactamase inhibitors for therapeutically effective anti-bacterial agents. Initially, the molecular docking-based score was used to reduce the chemical space of the selected dataset. Fourteen molecules were found to have more affinity towards the beta-lactamase in compared to the well-known anti-bacterial agent, Avibactam. Binding interactions analysis revealed the strong binding interactions between phytochemicals and catalytic amino residues. For further analysis, molecular dynamics (MD) simulations, density functional theory (DFT) and pharmacokinetics studies were performed. Parameters from MD simulations studies suggested that selected molecules are strong enough to retain in the active site in different orientations of the beta-lactamase. The orbital energies obtained from the DFT study was undoubtedly explained the potentiality of the selected compounds for being effective beta-lactamase inhibitors. The drug-likeness and acceptable pharmacokinetics parameters were observed using ADME analysis. Therefore, observations from the multiple pharmacoinformatics approach explained without any doubt that selected molecules are potential enough being promising anti-bacterial compounds. [Formula: see text] Communicated by Ramaswamy H. Sarma.
耐药性是细菌感染中一个未解决的主要问题。抗生素耐药性的不断发展极大地增加了细菌感染的危险。植物中的化学物质正成为治疗包括细菌感染在内的多种疾病的潜在有效治疗化学药物的主要来源。在本研究中，我们采用了基于药效学的方法对 200 多种已知植物化学物质进行了研究，以寻找有前途的β-内酰胺酶抑制剂，用于治疗有效的抗菌药物。最初，我们使用基于分子对接的评分方法来缩小所选数据集的化学空间。与著名的抗菌药物阿维巴坦相比，发现 14 种化合物对β-内酰胺酶具有更高的亲和力。结合相互作用分析揭示了植物化学物质与催化氨基酸残基之间的强结合相互作用。为了进一步分析，我们进行了分子动力学（MD）模拟、密度泛函理论（DFT）和药代动力学研究。MD 模拟研究的参数表明，所选分子足以在不同的β-内酰胺酶构象中保留在活性部位。DFT 研究中获得的轨道能无疑解释了所选化合物作为有效β-内酰胺酶抑制剂的潜力。通过 ADME 分析观察到药物相似性和可接受的药代动力学参数。因此，基于多种药效学方法的观察结果毫无疑问地表明，所选分子具有足够的潜力成为有前途的抗菌化合物。[公式：见正文]
