Identification of Novel Inhibitors of Fibroblast Growth Factor (FGF‐2) Binding to Heparin and Endothelial Cell Survival from a Structurally Diverse Carbohybrid Library.

Murphy, Peter; Pitt, Nigel; O'Brien, Alan; Enright, Philomena M.; Dunne, A; Wilson, Stephen J.; Duane, Rhona M; O’Boyle, Kathy M.

doi:10.1002/chin.200310189

Cited by 2 publications

(3 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 Anticancer agents that have been developed to target the FGFs include heparin-mimicking polysulfonated compounds, 2 suramin and the related suradistas, 3 and sulfated oligosaccharides. 4,5 There are no small molecule inhibitors of the FGFs in widespread clinical use as antiangiogenic agents, though recent studies using monosaccharides 6 and naphthalene sulfonate derivatives 7 demonstrate the promise of this approach. The work described in this paper is a part of our effort to design FGF inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2

Bytheway¹,

Cochran²

2004

J. Med. Chem.

View full text Add to dashboard Cite

A predictive relationship between calculated and observed binding affinities for the complexation of ligands to the fibroblast growth factors FGF-1 and FGF-2 based on molecular docking calculations is described. The majority of the ligands examined in this study have high conformational flexibility, and to account for this, multiple conformers were generated for each and subsequently used in flexible docking calculations. Two scoring functions, Gscore and Emodel, were used to quantify the protein:ligand interaction of which the Emodel score showed the best correlation with experimental binding energies. Both scoring functions, however, predicted similar locations for the ligand sulfate groups in the binding site. The van der Waals radii of nonpolar atoms of both the protein and ligand, which modify the effective sizes of both the protein binding site and the ligand, were also systematically altered by factors of 1.0, 0.9, and 0.8 in order to optimize the conditions for predictive docking. Least squares analyses of the Emodel scores against experimental binding energies yielded best r(2) values of 0.91 and 0.83 for FGF-1 and FGF-2, respectively, with slightly lower q(2) values. Optimized scale factor combinations in conjunction with the least squares lines of best fit based on the Emodel function were used to define a predictive model that was tested against ligands not included in the original set. Acceptable predictions of binding affinity were obtained for use in the initial screening of potential leadlike molecules for both FGF-1 and FGF-2.

show abstract

Section: Introductionmentioning

confidence: 99%

Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2

Bytheway¹,

Cochran²

2004

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Indeed, reported FGF-2 inhibitors are heterocycles tethered to glucuronide derivatives. 25 Perhaps the oxygenated side chain of 1e plays a role in the FGF-2 inhibition through mimicry of a carbohydrate residue.…”

Section: Resultsmentioning

confidence: 90%

“…There are obvious structural similarities between 1e and 5 , particularly the oxygen-containing side chain of both compounds. The FGF-2 molecular target plays an important role in cell growth and has been the target of antitumor agent design. – The fibroblast growth factors interact with the receptor tyrosine kinases (FGFRs) in conjunction with heparin-binding coreceptors. Indeed, reported FGF-2 inhibitors are heterocycles tethered to glucuronide derivatives .…”

Section: Resultsmentioning

confidence: 99%

Discovery of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition

et al. 2008

View full text Add to dashboard Cite

A series of substituted quinoline-5,8-diones were synthesized and evaluated as inhibitors of the chaperone protein Hsp90 using two assays: competition for binding to C-terminal ATP-binding site and competition for binding to N-terminal ATP-binding site. In addition, the ability of the compounds to induce the heat shock response was determined using a reporter fibroblast cell line. Of all the compounds assayed, only 6-aziridinyl-2-biphenylquinoline-5,8-dione induced a heat shock response and did so without interacting at the ATP binding sites of Hsp90. COMPARE analysis was carried out on quinoline-5,8-diones active in the National Cancer Institute's 60-cell line screen with the goal of discovering quinoline-5,8-dione structures that interact with other cellular targets (molecular targets) important for cancer chemotherapy. COMPARE analysis led to the discovery of a combretastatin-like quinoline-5,8-dione structure that, in fact, inhibited angiogenesis.

show abstract

Identification of Novel Inhibitors of Fibroblast Growth Factor (FGF‐2) Binding to Heparin and Endothelial Cell Survival from a Structurally Diverse Carbohybrid Library.

Abstract: Library. -(MURPHY*, P. V.; PITT, N.; O'BRIEN, A.; ENRIGHT, P. M.; DUNNE, A.; WILSON, S. J.; DUANE, R. M.; O'BOYLE, K. M.; Bioorg. Med. Chem. Lett. 12 (2002) 22, 3287-3290; Dep. Chem., Univ. Coll., Belfield, Dublin 4, Ire.; Eng.) -R. Langenstrassen 10-189

Cited by 2 publications

References 1 publication

Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2

Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2

Discovery of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition

Contact Info

Product

Resources

About