Inhibition structure-based design

SakolFJi McCluskey A (2004) Protein phosphatase inhibition structure based design. Towards new therapeutic agents. Curr Pharm... 

Nelfinavir. Using structure-based design in conjunction with predicted oral pharmacokinetics, NFV was identified and found to have potent inhibition of HIV-1 in vitro with an IC50 in the 2nM range (Kaldor et al. 1997). Clinical trials of NFV revealed robust and sustained reductions in HIV-1 RNA with over half of all subjects attaining a persistent 1.6 logxo reduction at 12 months, in conjunction with a mean increase in CD4 cells of 180-200 per mm (Markowitz et al. 1998). In subjects... 

Even though the above mentioned small molecules exhibit IL-1 inhibition none of them were discovered based on defined functional or structural aspects. An understanding of the three-dimensional structure of IL-ls and their receptors, by themselves or in complexes, will form a very strong foundation for structure-based design of more specific and potent IL-1-based immunomodulators. 

Miller, D.J., Ravikumar, K., Shen, H., Suh, J.K., Kerwin, S.M. and Robertas, J.D. (2002) Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition. J Med Chem, 45, 90-98. 

The anthraquinone derivative (2) represents the first example from 1997, with numerous others following in rapid succession, including the dibenzo-phenanthroline derivatives and tri-substituted acridines (3), which were reported to inhibit telomerase action in tumour cell lines with IC50 values of up to 28 and 60 nM, respectively. The tri-substituted acridines (3) were developed from the simple acridine (4) on the basis of structure-based design principles to maximise the quadruplex binding affinity. Thus, inhibition of telomerase by these compounds appears to be correlated to selective stabilisation of the human DNA quadruplex structure. Tetra-(A-methyl-4-pyridyl)-porphyrins... 

Fretz, H., Furet, P., Garcia-Echeverria, C., Rahuel, J. and Schoepfer, J. (2000) Structure-based design of compounds inhibiting Grb2-SH2 mediated protein-protein interactions in signal transduction pathways. Curr. Pharm. Des. 6 1777-1796. 

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