Abstract：
The biofilm formation is still prevalent mechanism of developing the drug resistance in the Pseudomonas aeruginosa, gram-negative bacteria, known for its major role in nosocomial, ventilator-associated pneumonia (VAP), lung infections and catheter-associated urinary tract infections. As best of our knowledge, current study first time reports the most potent inhibitors of LasR, a transcriptional activator of biofilm and virulence regulating genes in, Pseudomonas aeruginosa LasR, utilizing newly functionalized imidazoles (5a-d), synthesized via 1,3-dipolar cycloaddition using click approach. The synthesized ligands were characterized through Mass Spectrometry and 1H NMR. The binding potency and mode of biding of ligands. Quantum Mechanical(QM) methods were utilized to investigate the electronic basis, HOMO/LUMO and dipole moment of the geometry of the ligands for their binding potency. Dynamics cross correlation matrix (DCCMs) and protein surface analysis were further utilized to explore the structural dynamics of the protein. Free energy of binding of ligands and protein were further estimated using Molecular Mechanical Energies with the Poisson-Boltzmann surface area (MMPBSA) method. Molecular Docking studies revealed significant negative binding energies (5a - 10.33, 5b -10.09, 5c - 10.11, and 5d -8.33 KJ/mol). HOMO/LUMO and potential energy surface map estimation showed the ligands(5a) with lower energy gaps and larger dipole moments had relatively larger binding potency. The significant change in the structural dynamics of LasR protein due to complex formation with newlyfunctionalized imidazoles ligands. Hydrogen bond surface analysis followed by MMPBSA calculations of free energy of binding further complemented the Molecular docking revelations showing the specifically ligand (5a) having the relatively higher energy of binding(-65.22kj/mol).Communicated by Ramaswamy H. Sarma.
摘要：
生物膜的形成仍然是铜绿假单胞菌耐药性发展的普遍机制,革兰氏阴性菌,以其在医院中的主要作用而闻名，呼吸机相关性肺炎(VAP),肺部感染和导尿管相关尿路感染。据我们所知,目前的研究首次报道了LasR最有效的抑制剂，生物膜和毒力调节基因的转录激活因子，铜绿假单胞菌LasR,利用新官能化的咪唑（5a-d），使用点击方法通过1,3-偶极环加成合成。通过质谱和1HNMR对合成的配体进行了表征。配体的结合效能和结合方式。量子力学(QM)方法被用来研究电子基础，HOMO/LUMO和偶极矩的几何形状的配体的结合效力。进一步利用动力学互相关矩阵(DCCM)和蛋白质表面分析来探索蛋白质的结构动力学。使用分子机械能和泊松-玻尔兹曼表面积(MMPBSA)方法进一步估计配体和蛋白质的结合自由能。分子对接研究揭示了显著的负结合能(5a-10.33、5b-10.09、5c-10.11和5d-8.33KJ/mol)。HOMO/LUMO和势能表面图估计显示具有较低能隙和较大偶极矩的配体(5a)具有相对较大的结合效能。由于与新官能化的咪唑配体形成复合物，LasR蛋白的结构动力学发生了显着变化。氢键表面分析,然后MMPBSA计算结合自由能进一步补充了分子对接的启示,显示特异性配体(5a)具有相对较高的结合能(-65.22kj/mol)。由RamaswamyH.Sarma沟通。
