Hydrophobic binding description

Since hydrophobic interactions contribute largely to the DHFR-inhibitor binding, it was deemed interesting to apply ab initio methods to the description of aromatic-aromatic interactions. 

It is important to emphasize that the introduction of a spacer should never affect the binding characteristics of the support. The selected spacer must not introduce any charges and should not be sufficiently hydrophobic to cause any kind of non-specific interaction. Several molecules can fulfill this demand but only a few of them are regularly used. Most of these contain terminal amino or carboxylic groups. In particular these are diaminodipropyl amine, 6-aminocapronic acid, 1,6-diaminohexane, ethylenediamine, l,3-diamino-2-propanol, succinic acid, 1,4-butanediol diglycidyl ether, and others [96]. Extensive description of other bifunctional reagents can be found in the book of Wong [89]. 

So far we have taken into account only the steric and electrostatic fit of congeneric drug molecules that bind at the same receptor site. This is clearly not sufficient if one aims towards a more detailed description of the structural properties of a receptor. Besides the already mentioned characteristics, hydrophobic areas, regions of charge transfer or several types of different polar interactions can also be distinguished. A receptor map which contains three-dimensional information of this kind is very helpful in the interpretation and understanding of known experimental results but also, which is even more desirable, for the prediction of new, hitherto unknown structures. 

Theophylline binds to a subpocket of the active site and appears to be sandwiched between a phenylalanine and a valine via hydrophobic bonds. Its binding affinity is reinforced by hydrogenbonding between a tyrosine and N-7 and a glutamine and 0-6 of the xanthine ring system. There are more than 11 families of PDEs, and studies have shown that theophylline binds in a similar manner to both the PDE4 and PDE5 family isoforms (30). (For a more detailed description of PDE subtypes and their inhibitors, see Chapter 17.)... 

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