Affinity, enzymes

Kuyper LF, Roth B, Baccanari DP, Ferone R, Beddell CR, Champness JN et al. Receptor-based design of dihydrofolate reductase inhibitors comparison of crys-tallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues. J Med Chem 1982 25 1120-2... 

Quantitative assessment of enzyme affinity for various members of these chemical series is critical for development of a meaningful understanding of SAR and ultimately for compound optimization for clinical use. 

In an ideal situation a structural series of compounds will have unlimited cell permeability, and one can therefore expect a strict correlation between rank-order enzyme affinity (as measured by K, values) and the EC50 for cellular effects (the EC50 is the cellular or organismal equivalent of the in vitro IC50 i.e., the EC50 is the con-... 

Often very subtle structural changes in a compound can cause significant changes in target enzyme affinity. Sometimes addition of a single methylene group... 

In some cases, a changed or enhanced regioselectivity can be accomplished by partially protected acceptors, especially those with the C-6 position blocked. From the most trivial point of view, this approach limits the choice of the available acceptor hydroxyls.75,91,92 The C-6 modification of the acceptor may also considerably change the enzyme affinity (Scheme 4).92... 

The adsorption should be strong enough to insure no enzyme leakage under process operation. In the eharaeterization of a carrier material, adsorption isotherms of enzyme adsorbed to the earrier ean illustrate the enzymes affinity towards the carrier material and the maximum amount of enzyme, whieh ean be adsorbed on the material (Rexova-Benkova, 1992 and Gitlesen, Bauer Adlerereutz, 1997). 

CGTases (EC 2.4.1.19) are bacterial enzymes that facilitate the biosynthesis of cyclodextrins from starch through intramolecular transglucosylation. The primary structures of most of these enzymes have been published, and the three-dimensional structure of Bacillus circulans CGTase has been established. Studies of transglucosylation molecular mechanism have indicated that amino acids such as histidine and tryptophan are implicated in such mechanisms. Nitration of CGTase with TNM induces a loss of enzyme activity, a decrease in enzyme affinity towards the (i-CD copolymer, and a loss of tryptophan fluorescence (Villette etal. 1993). 

Resistance Nonproliferating cells are resistant to methotrexate. Resistance in neoplastic cells can be due to amplification (production of additional copies) of the gene that codes for dihydrofolate reductase resulting in increased levels of this enzyme. The enzyme affinity for MTX may also be diminished. Resistance can also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated transport responsible for pumping methotrexate into the cell. 

Table 2 Nuclear receptors (NR) for enzyme inducers. Enzyme inducers are now known to act as ligands to nuclear receptors, leading to gene activation and increased synthesis of the enzyme. Affinity of inducers to die receptors is now known to be responsible for the differential induction potential and can explain die observed species-differences in induction. The receptors tabulated are aryl hydrocarbon receptors (AhR), constituitively androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR). The isoforms in bold type are the major isoform regulated by the corresponding receptors.

The organophosphorus insecticides are all structurally related and undergo similar reactions. The chemical classification of the most widely used compounds of this type is given in Table V. These compounds can also be differentiated on the basis of whether they are largely effective per se or undergo oxidative conversions in plants or animals. All are inhibitors of the enzyme, cholinesterase. Their potency depends not only upon their intrinsic enzyme affinity but also on anticholinesterase properties acquired through in vivo metabolism. 

An extension of enzyme immunoassay is the enzyme affinity assay applicable to studies of nonimmunological interactions. This is already exemplified by the measurement of hormone using its receptor and by our studies on the interaction of fibronectin with collagen. - Assays of these and similar principles might well become a new area of expression for EIA. 

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