Novel Naphthalene-N-sulfonyl-D-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme
Novel Naphthalene-N-sulfonyl-D-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme
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DOI：
10.1021/jm800762u
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发表时间：
2008-12-11
影响因子：
7.3
通讯作者：
Gobec, Stanislav
中科院分区：
文献类型：
--
作者：
Humljan, Jan;Kotnik, Miha;Gobec, Stanislav
Mur连接酶在肽聚糖的生物合成中具有重要作用，并且它们代表了用于设计新型抗菌剂的有吸引力的靶标。MurD（UDP-N-乙酰胞壁酰-L-丙氨酸：D-谷氨酸连接酶）是Mur连接酶系列中的第二个酶，它催化D-谷氨酸（D-Glu）与胞质中间体UDP-N-乙酰胞壁酰-L-丙氨酸（UMA）的加成。由于D-Glu对MurD具有很高的结合亲和力，我们合成了一系列N-取代的D-Glu衍生物，并对其进行了生物化学评价。这使我们能够探索结构-活性关系。作为潜在的过渡态类似物合成的取代的萘-N-磺酰基-D-Glu抑制剂显示出80至600 μ M的IC 50值。此外，MurD与四种新型抑制剂复合的高分辨率晶体结构揭示了MurD活性位点内抑制剂的结合模式的细节。构效关系和共晶结构构成了进一步开发这种结构类别的新型MurD抑制剂的极好起点。
Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition Of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity Of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships. The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition-state analogues, displayed IC50 values ranging from 80 to 600,mu M. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.