| This research work focuses on the determination for the first time of the 3D solution structure of potent anticancer drug suramin, investigation of its conformational properties, and use of this structure to propose molecular models for its interaction with and inhibitory effect exerted upon two growth factors: bFGF and PDGF-BB.; Joint use of 2D NMR and modeling techniques revealed C{dollar}sb2{dollar} symmetry and an unusually high segmental flexibility at the level of the second pair of secondary amides that anchor the two naphthalene systems. Free rotations about the C(phenyl)-C(carbonyl) and C(naphthalene)-C(amide) bonds and rotation of each sulfonate group about C(naphthalene)-S(sulfone) bonds appear to direct the orientation of these charged groups, thus accounting for the ability to interact non-specifically with a variety of structurally and functionally diverse proteins.; Docking simulations in the Amber force field with a genetic algorithm (GA) were carried out by allowing the suramin molecule to adjust its conformation to the protein surface (bFGF and PDGF), while, at the same time, permitting the exposed basic residues to adjust their molecular conformation to facilitate the formation of salt bridges and H-bonds with suramin. In both cases, two suramin molecules "engulf" one molecule of protein. GA generated docking scores seem to indicate good shape complementary associated with sufficient polar contacts to stabilize the interactions between suramin and each of the two proteins. Only two sulfone functions from each naphthalene group participate in the ligation process. The two complexes differ in that, in view of its internal molecular flexibility suramin is "capable" and actually "uses" two different conformers to dock to the growth factors: "open stance horse-shoe" for bFGF, and "closed stance horse-shoe" for PDGF.; Both models are consistent with most experimentally determined properties (such as the 2:1 binding stoichiometry), and, account for the molecular mechanisms responsible for the inhibitory effect suramin exerts upon these factors, essentially by preventing attachment of cognate receptors.; Results of these structure-biological investigations may be used to design suramin analogs with increased binding specificity to selected cytokines such as bFGF and PDGF, thus improving the therapeutic vs toxicity ratio, and, consequently, the efficiency of this pharmaceutical. |
