Metabolism binding affinity

Kinetics is the branch of science concerned with the rates of chemical reactions. The study of enzyme kinetics addresses the biological roles of enzymatic catalysts and how they accomplish their remarkable feats. In enzyme kinetics, we seek to determine the maximum reaction velocity that the enzyme can attain and its binding affinities for substrates and inhibitors. Coupled with studies on the structure and chemistry of the enzyme, analysis of the enzymatic rate under different reaction conditions yields insights regarding the enzyme s mechanism of catalytic action. Such information is essential to an overall understanding of metabolism. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

ArQule provides professional services and products including metabolism models for CYP 3A4, 2D6, and 2C9. The metabolism models are based on combined empirical/quantum chemical approaches and are aimed at predicting the site of metabolism, enzyme-substrate binding affinities (2D6 and 2C9), and relative rates of metabolism at discrete sites within a molecule (274). 

At the molecular level, the compound would be screened for activity on the target, for example, receptor binding affinity to cell membranes containing the homologous animal receptors (or if possible, on the cloned human receptors). Early studies would be done to predict effects that might later cause undesired drug metabolism or toxicologic complications. 

Lewis, D.F. and Ito, Y. (2010) Human CYPs involved in drug metabolism structures, substrates and binding affinities. Expert Opin. Drug Metab. Toxicol, 6 (6), 661-674. 

Enantiomeric Pairs. Enantioselective differences in absorption, metabolism, clearance, drug-macromolccule binding affinity, and other factors, which culminate in the obscivcd enantioselective efficacy chiral drugs, are considered. 

However, the binding affinities of 197,206 and 207 [0.3%, 0.1% and <0.01%, respectively, relative to oestradiol (100%)] for the oestrogen specific acceptor protein of the rat uterus suggest that a steric or an electronic effect, rather than metabolic instability, is responsible for the absence of oestrogenic activity in these compounds. But a clear answer cannot be given because biological data of the direct 6,6-dimethyl-6-carba-analogues are not known so far. 

CYP is a family of different enzymes. Each variation has a slightly different function, but all are able to accept substrates with a range of structure. Their active sites tend to be broad and shallow so that almost any compound can tit to some degree. Table 4.3 shows the variety of reactions that can be performed by CYP3A4, a common form of CYP.21 Despite unrelated substrate structures, the Km values (binding affinities) are fairly uniform. A more thorough treatment of drug metabolism will be presented in Chapter 8. 

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