ISSN:
1573-7209
Keywords:
Anti-angiogenic agent
;
growth factors
;
molecular conformation
;
molecular modeling
;
nuclear magnetic resonance
;
suramin
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The conformational requirements of suramin for its binding to basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) were examined by molecular modeling and docking simulations using the conformational features of suramin determined by the present proton nuclear magnetic resonance (1H-NMR) studies and the crystal structures of growth factors reported previously. The assignment of resonances of suramin to individual protons was accomplished by the combined analysis of the coupling constants, two-dimensional correlated spectroscopy (COSY) and nuclear Overhauser effect spectroscopy (NOESY). The NOESY data obtained for suramin were utilized in a conformational search algorithm with constraints to generate a family of conformers which were further refined by restrained energy minimization. A family of nine conformers generated by restrained modeling falls primarily into one of two categories, either the conformer's two naphthyl rings are far apart, ∼28–30 Å, from one another or the conformer's two naphthyl rings are relatively close, ∼16–18 Å. The NMR data provide evidence for the presence of more than one conformer in solution. The modeling and docking simulation studies suggest that suramin binds efficiently to bFGF and PDGF by an induced-fit mechanism, wherein suramin complements bFGF or PDGF by adjusting its conformational freedom around the two pairs of single bonds that link the middle phenyl rings to the secondary amide backbone. The interaction of suramin with bFGF or PDGF primarily involves ion-pair, hydrophobic and hydrogen bonding interactions, in addition to van der Waals' contacts. The results indicate that suramin not only sterically blocks the receptor binding loop of the growth factors, but also competes for the binding sites of agonists such as heparin. The results suggest that suramin's propensity to bind to several polypeptides of varying size and structure is due to its conformational flexibility. Collectively, the data emphasize that conformationally constrained suramin analogs that selectively and competitively target angiogenic growth factors could be designed to reduce non-specific binding and, accordingly, toxicity.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1009244623717
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