By Fuyuhiko Tamanoi
This specified quantity of The Enzymes is specified towards researchers in biochemistry, molecular and mobilephone biology, pharmacology, and melanoma. This thematic quantity discusses inhibitors of the Ras superfamily G-proteins.
Key features:
* Contributions from best authorities
* Informs and updates on the entire newest advancements within the box
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Extra resources for Inhibitors of the Ras Superfamily G-proteins, Part A, Volume 33
Sample text
The Kd determinations were important in the hit-to-lead process, as at this time no biochemical readout was available for compounds with the low binding affinities of between 10 and 1000 μM associated with fragment ligands. With an upper limit due to ligand solubility and a lower limit due to intermediate exchange, this process was applicable for an affinity range from single-digit millimolar to double-digit micromolar. These values are often not covered in the affinity range of a typical HTS-based assay but very well matched for fragment-based discovery.
2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature. 1995;375:554–560. 21. Paduch M, Jelen F, Otlewski J. Structure of small G proteins and their regulators. Acta Biochim Pol. 2001;48:829–850. 22. Thapar R, Williams JG, Campbell SL. NMR characterization of full-length farnesylated and non-farnesylated H-Ras and its implications for Raf activation. J Mol Biol. 2004;343:1391–1408. 23. Smith MJ, Neel BG, Ikura M. NMR-based functional profiling of RASopathies and oncogenic RAS mutations.
As a rule, all measured STD intensities should be well under 15% as defined by the ratio between on- and off-resonance 1D spectra [57]. This step eliminated promiscuous binding and aggregated fragments. It also improved the library quality for subsequent X-ray crystallography, where high compound concentration is required. The final step was to formulate the compound mixtures for primary screening. The above-described properties used for the selection of each compound in the fragment library were used to calculate the three top principal components for these properties in the fragment set.