Modular binding approach

Different prediction models have been reported including (i) pharmacophore models that take into account structural features, (ii) linear discriminant models that do not consider structural features, (iii) a modular-binding approach, and (iv) rule-based approaches. The focus of the following discussion is to identify the most important descriptors in the different approaches and relate them to the physicochemical parameters determined in the different P-gp assays. 

Figure 22. (a) A fragment of the photosynthetic reaetion center with the three eomponents Speeial Pair (SP), Accessory Baeteriochlorophyll (BCh), and Bacteriopheophytin (BPh). Photoindueed electron transfer from SP to BPh takes place at a i lobal rate of (3 ps). (b) Prineiple of the modular mimetic approach. D and A are the donor and aeceptor porphyrins, respectively. M is an eleetron transfer mediator whose introduction between D and A can be realized via coordination of a metal center (solid circle) which will also bind the chelating part of the bisporphyrin spacer. 

Modular design. Synthetic molecules were constructed of multiple, closely related nonsymmetric repeat units that can be covalently attached from either end. This approach allows rational design of various congeners, controlling their physical properties, such as iron-binding capacities and partition coefficients (lipophilic/hydrophilic... 

We will demonstrate in this chapter our approach towards modular receptors for complexation of biologically relevant peptides in water. A new binding motif for carboxylates, the guanidiniocarbonyl pyrroles, has been designed this enables the formation of stable ion pairs even in aqueous solvents. By a stepwise elongation of this binding motif with additional interaction sites receptors are obtained that bind not only carboxylates but also single amino acids, both side-chain- and ste-reoselectively, and even tetrapeptides. 

The sensor developed by Gawley and co-workers is based on de Silva s modular approach comprises an azacrown ether linked to a fluorophore by a short link. The molecule combines the aza[18]crown-6 recognition element with a fluorescent coumaryl group attached by a methylene spacer. In tests it was shown to bind to saxitoxin with a binding constant on the order of 105 M 1, even in a phosphate buffer at physiological pH and concentrations of sodium and potassium, and could detect levels of the toxin down to 1(T7 M. Subsequent modification of the sensor allowed it to be linked to the surface of a quartz slide to allow the fluorescent response to concentrations of saxitoxin between 10-4 and 10-6 M to be detected via a fibre optic system. This level of sensitivity is comparable to the current mouse bioassay that requires the inoculation of a large number of animals to determine the concentration of saxitoxin present in the test sample [25],... 

The importance of this approach to drug delivery is that it is modular so that variations can be made to each component. Thus the adamantane substituents can be varied to elicit different biological responses or bind to other protein receptors. The polymer can be varied so that it binds to different guest molecules, incorporates different macrocycles or unravels under different conditions. Finally, and most importantly, the guest can be varied from the large, charged siRNAs down to small drug molecules. 

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