1234 Modern End Game Studies With Appendix Containing 24 by M.A.; LOMMER, H.M. SUTHERLAND

1234 Modern End Game Studies With Appendix Containing 24 by M.A.; LOMMER, H.M. SUTHERLAND

By M.A.; LOMMER, H.M. SUTHERLAND

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Cki degradadon htty add bloaynme-I. 'Figure 3. Proteomic analysis of the effects of clofibrate on the citric acid cycle in the rat liver. Sue-em"1 "'I" l 'l~l\1 Fuma,ate Malilte + ~ Gtyoxyla1. & dk'arboaylabt metabolism ~ ~ .......... ,te - ;,0 ec ~ ~ ::: '- N 00 2 Proteomics 29 of other metabolic pathways, were simultaneously monitored, leading to a considerably broader insight into this drug's effects on cellular metabolism. Such a system-wide view is essential for rational decision-making to advance lead compounds into development.

Such a system-wide view is essential for rational decision-making to advance lead compounds into development. 6 Preclinical toxicology Toxicological screening is an important early stage in the development of a drug when the mode of action has been validated. Many initially promising drugs fail at this stage, but traditional toxicological screens (see Chapter 13) have been both laborious and difficult to interpret. Proteomics has great potential in early toxicological screening, since it is anticipated that drug toxicity will produce a limited array of proteomic signatures that can be documented and used to screen the toxicological properties of novel candidates.

This so-called 1 percent accepted mutation (lPAM) was then extrapolated to other distances. At 250PAMs (the general standard), for example, approximately one in five amino acids remain unchanged. This average, of course hides the fact that the amino acids differ in their mutability, with almost half of all tryptophans and cysteines remaining unchanged. One factor that might question the credibility of this scheme is the small size of the dataset used. In an attempt to enhance the accuracy of the PAM matrices, Jones et al.

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