Blocking the catalytic mechanism of MurC ligase enzyme from Acinetobacter baumannii: An in Silico guided study towards the discovery of natural antibiotics
Blocking the catalytic mechanism of MurC ligase enzyme from Acinetobacter baumannii: An in Silico guided study towards the discovery of natural antibiotics
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DOI：
10.1016/j.molliq.2019.02.051
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发表时间：
2019-05-01
影响因子：
6
通讯作者：
Azam, Syed Sikander
中科院分区：
文献类型：
--
作者：
Ahmad, Sajjad;Murtaza, Uzair Ali;Azam, Syed Sikander
鲍曼不动杆菌是对包括高效碳青霉烯类和第三代头孢菌素在内的多种抗生素耐药的最关键的病原菌。针对所述病原体的独特途径的新型抗生素可以降低由于其感染而对目前的抗生素不具抵抗力的死亡率。在这里，我们探索了一个天然化合物的文库，该文库首先筛选出类药物，然后筛选出类铅分子，最后将其用于基于结构的虚拟筛选，以确定最有希望的MurC连接酶配体结合(LB)区域的抑制剂。观察到抑制剂(1‘-((2H-imidazol-2-yl)methyl)-N-(pyridin-2-yl)-1’，2‘-dihydro-[4，4’-bipyridin]-2-amine)的构象针对预期的LB的最保守的和催化关键的残基以及MurC的三磷酸腺苷结合域。这种多结构域抑制剂显示出良好的药代动力学特征，因此很可能在未来具有安全有效的治疗应用。水溶液中的分子动力学模拟进一步支持了该化合物对包含强氢键的目标位置的高亲和力。在残基水平上，径向分布函数(RDF)和轴向分布函数(AFD)表明Asp334是驱动化合物识别、结合和活性的最关键的氨基酸。通过分子力学Poisson-Boltzmann表面积(MMPBSA)、分子力学广义Born表面积(MMGBSA)和基于Watswp的结合自由能计算验证了络合物的稳定性。该体系具有很高的稳定性：MMGBSA(-48.45kcal/mol)和MMPBSA(-3.62kcal/mol)的总结合能。在MurC-抑制剂结合中，柱状相互作用占主导地位(-336.90千卡/摩尔)，其次是范德华能(-45.52千卡/摩尔)。WatSwp估算的绝对结合自由能为-43.2kcal/mol，说明络合物具有较高的稳定性。筛选后的支架可用于官能团取代，实现进一步的先导优化。(C)《2019年》，爱思唯尔出版。
Acinetobacter baumannii belongs to the most critical group of bacterial pathogens that are resistant to large number of antibiotics, including the highly effective carbapenems and third generation cephalosporins. Novel antibiotics targeting unique pathways of the said pathogen could reduce the mortality rate due to its infections that are impervious to the current antibiotics. Herein, we explored a library of natural compounds that was filtered first for drug-like, followed by lead-like molecules, which were finally utilized in structure based virtual screening to identify the most promising inhibitor for the Ligand binding (LB) domain of MurC ligase enzyme. The inhibitor (1'-((2H-imidazol-2-yl)methyl)-N-(pyridin-2-yl)-1',2'-dihydro-[4,4'-bipyridin]-2-amine) was observed with a conformation to target most conserved and catalytically critical residues of both the intended LB as well as the ATP binding domain of MurC. This multi-domain inhibitor revealed to have an excellent pharmacokinetics profile thus likely to have safe and effective therapeutic applications for the future. Molecular dynamics simulation in aqueous solution further supported the high affinity of the compound for the target site involving strong hydrogen bonding. At residue level, radial distribution function (RDF) and axial distribution function (AFD) illustrated Asp334 as the most critical amino acid that drives recognition, binding, and activity of the compound. The complex stability was validated by subjecting it to Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA), Molecular Mechanics Generalized Born Surface Area (MMGBSA) and WaterSwap based binding free energy calculations. The system was observed with high stability: total binding energy in MMGBSA (-48.45 kcal/mol) and MMPBSA (-3.62 kcal/mol). The columbic interactions were noticed to dominate (-336.90 kcal/mol), followed by van der Waals energies (-45.52 kcal/mol) in MurC-inhibitor binding. The absolute binding free energy estimated by WaterSwap was -43.2 kcal/mol, depicting higher complex stability. The screened scaffold might be used in functional groups substitution to achieve further lead optimization. (C) 2019 Published by Elsevier B.V.