Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
Centre for Theoretical Studies, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
J Mol Graph Model. 2022 Sep;115:108215. doi: 10.1016/j.jmgm.2022.108215. Epub 2022 May 20.
Staphylococcus aureus causes a wide range of common diseases in both community-acquired and hospital-acquired environments. The treatment becomes challenging due to the emergence of multi-drug resistant strains such as Methicillin-Resistant Staphylococcus aureus (MRSA). This study aims to find some drugs that can be used in repurposing. Virtual screening has been performed against S. aureus FemX using 1,918 FDA-approved drugs, which provides the top 10 drugs with good binding affinity. These drugs are re-docked to understand their interaction patterns with FemX. Docking study shows a high score for three drugs, Lumacaftor, Dihydroergocornine and Olaparib, and they are selected for molecular dynamics and quantum mechanical analysis. Molecular dynamics calculation shows that drug-FemX forms a stable structure compared to apo-FemX. Besides, the free energy landscape reveals that drug-protein complexes possess a single global minimum indicating their thermodynamic stability. MM/GBSA calculations show that Lumacaftor, Dihydroergocornine and Olaparib have the binding free energy of -30.03, -19.22 and -16.54 kcal/mol, respectively. The analysis of the wavefunctions from quantum chemical calculations reveals the presence of non-covalent interactions between drug and receptor, dominated by aromatic π-π interactions. The drug-receptor interaction energy estimated from quantum mechanical methods suggests an important role of dispersion interactions in stabilizing the drug molecules with FemX. The hierarchy of computational methods of increasing accuracy employed in this work finds Lumacaftor to be the most potent inhibitor against FemX.
金黄色葡萄球菌在社区获得性和医院获得性环境中引起广泛的常见疾病。由于出现了耐甲氧西林金黄色葡萄球菌（MRSA）等多种耐药菌株，治疗变得具有挑战性。本研究旨在寻找一些可用于重新利用的药物。使用 1918 种已获得 FDA 批准的药物对 S. aureus FemX 进行了虚拟筛选，提供了与 FemX 具有良好结合亲和力的前 10 种药物。这些药物被重新对接以了解它们与 FemX 的相互作用模式。对接研究显示三种药物（Lumacaftor、二氢麦角胺和奥拉帕利）的得分较高，它们被选中进行分子动力学和量子力学分析。分子动力学计算表明，与无配体的 FemX 相比，药物-FemX 形成了稳定的结构。此外，自由能景观表明药物-蛋白质复合物具有单个全局最小值，表明它们具有热力学稳定性。MM/GBSA 计算表明，Lumacaftor、二氢麦角胺和奥拉帕利的结合自由能分别为-30.03、-19.22 和-16.54 kcal/mol。从量子化学计算中波函数的分析表明，药物和受体之间存在非共价相互作用，主要由芳香族π-π相互作用主导。从量子力学方法估计的药物-受体相互作用能表明，色散相互作用在稳定与 FemX 的药物分子方面起着重要作用。在这项工作中，随着准确性的提高，计算方法的层次结构发现 Lumacaftor 是对 FemX 最有效的抑制剂。
