Inhibition of tumor necrosis factor-alpha (TNF-alpha)/TNF-alpha receptor binding by structural analogues of suramin.
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.
Mancini
F
F
Angelini Ricerche, S. Palomba-Pomezia, Rome.
Toro
C M
CM
Mabilia
M
M
Giannangeli
M
M
Pinza
M
M
Milanese
C
C
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013498:Suramin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014344:Trypanocidal Agents; D014409:Tumor Necrosis Factor-alpha; D013498:Suramin