Mancini F, Toro C M, Mabilia M, Giannangeli M, Pinza M, Milanese C
Angelini Ricerche, S. Palomba-Pomezia, Rome.
Biochem Pharmacol. 1999 Sep 1;58(5):851-9. doi: 10.1016/s0006-2952(99)00150-1.
Suramin, a symmetrical polysulfonated urea derivative, promotes the dissociation of trimeric human tumor necrosis factor-alpha (TNF-alpha) into biologically inactive subunits and prevents the interaction of TNF-alpha with its cellular receptors. The aim of this work was to identify compounds structurally related to suramin which inhibit the binding of TNF-alpha to its receptor. Molecular modeling studies were performed on suramin and TNF-alpha molecules and likely interaction sites were identified in the docked complex. On this basis, Evans blue, trypan blue, sulfonazo III, beryllon II, and 1,3,6-naphthalenetrisulfonic acid trisodium salt were identified as polysulfonated compounds endowed, to various extents, with the structural characteristics responsible for interaction with TNF-alpha. N,N-bis(3,5-di-tert-butylphenyl)-3,4,9,10-perylenedicarboximide was used as an unrelated structure. The capacity of these molecules to inhibit the binding of TNF-alpha with its receptor p55 was tested in vitro by means of a specific immunoenzymatic assay using suramin as reference compound. Evans blue and trypan blue inhibited TNF-alpha/p55 binding with an IC50 of 0.75 and 1.00 mM, respectively (suramin IC50: 0.65 mM); no effect was observed with the other molecules. Molecular modeling analyses on Evans blue and trypan blue docked into the TNF-alpha molecule support these experimental results by demonstrating that these compounds share with suramin a similar binding mode to TNF-alpha. The results of this work provide a new insight into and useful hints for the design of new chemical entities endowed with a potent and selective activity on TNF-alpha.
苏拉明是一种对称的多磺酸化尿素衍生物，它能促进三聚体人肿瘤坏死因子-α（TNF-α）解离为无生物活性的亚基，并阻止TNF-α与其细胞受体相互作用。本研究的目的是鉴定与苏拉明结构相关的化合物，这些化合物可抑制TNF-α与其受体的结合。对苏拉明和TNF-α分子进行了分子模拟研究，并在对接复合物中确定了可能的相互作用位点。在此基础上，伊文思蓝、台盼蓝、磺基偶氮III、铍试剂II和1,3,6-萘三磺酸三钠盐被鉴定为多磺酸化化合物，它们在不同程度上具有与TNF-α相互作用的结构特征。N,N-双(3,5-二叔丁基苯基)-3,4,9,10-苝二甲酰亚胺用作无关结构。通过使用苏拉明作为参考化合物的特异性免疫酶测定法，在体外测试了这些分子抑制TNF-α与其受体p55结合的能力。伊文思蓝和台盼蓝抑制TNF-α/p55结合的IC50分别为0.75和1.00 mM（苏拉明的IC50为0.65 mM）；其他分子未观察到效果。对对接至TNF-α分子中的伊文思蓝和台盼蓝进行的分子模拟分析表明，这些化合物与苏拉明具有相似的与TNF-α的结合模式，从而支持了这些实验结果。本研究结果为设计对TNF-α具有强效和选择性活性的新化学实体提供了新的见解和有用的提示。
