Inhibition of tumor necrosis factor-α (TNF-α)/ TNF-α receptor binding by structural analogues of suramin§§Abbreviations: TNF-α, tumor necrosis factor-α; and MC/EM, MonteCarlo/energy minimization.

Suramin, a symmetrical polysulfonated urea derivative, promotes the dissociation of trimeric human tumor necrosis factor-α (TNF-α) into biologically inactive subunits and prevents the interaction of TNF-α with its cellular receptors. The aim of this work was to identify compounds structurally related to suramin which inhibit the binding of TNF-α to its receptor. Molecular modeling studies were performed on suramin and TNF-α 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-α. 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-α 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-α/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-α molecule support these experimental results by demonstrating that these compounds share with suramin a similar binding mode to TNF-α. 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-α.