Article
Computational Analysis of the Interactions Between the Angiogenesis Inhibitor PD173074 and Fibroblast Growth Factor Receptor 1
Journal of Theoretical and Computational Chemistry
(2003)
Abstract
We have carried out computational sensitivity analysis to analyze the interactions between the inhibitor PD173074 and FGFR1 in order to identify the determinants of their recognition and generate insights into further refining the inhibitor. The analysis has identified the parts of the inhibitor that are already useful for binding, e.g. the part that recognizes the linker connecting the N-terminal and C-terminal lobes of the kinase domain. These parts are profitably kept during a lead optimization process. The analysis has also pointed out regions of the inhibitors that may be useful to modify to improve its binding affinity, e.g. the dimethoxyphenyl ring. Comparative structural analysis of the binding pocket of almost 400 protein kinases also suggests that modifying the dimethoxyphenyl moiety might improve selective binding. Selectivity may be achieved not only by introducing groups to the 3 and 5 positions but also to the 1 and 6 positions. Replacing the tertiary amines by hydrocarbon might also improve binding affinity.
Keywords
- Computational sensitivity analysis,
- continuum-solvent binding energy calculations,
- comparative sequence/structure analysis
Disciplines
Publication Date
January 3, 2003
DOI
10.1142/S0219633603000392
Citation Information
Kristin Tøndel, Chung F. Wong and J. A. Mccammon. "Computational Analysis of the Interactions Between the Angiogenesis Inhibitor PD173074 and Fibroblast Growth Factor Receptor 1" Journal of Theoretical and Computational Chemistry Vol. 2 Iss. 1 (2003) p. 43 - 56 Available at: http://works.bepress.com/chung-wong/45/