Promiscuous interactions

As an example of a promiscuous interaction, the binding site of the complex formed between erythromycin and cytochrome P450 3A4 [26] is shown in Figure 20.4b. Characteristic interactions of this complex are the following ... 

Drugs with simple or common pharmacophores cannot discriminate small differences among binding sites. Pharmacophores for ADME/Tox proteins are generally not complex [39], By contrast, drugs with complex or unusual pharmacophores have the potential to bind selectively to target proteins. Therefore chemical modification intended to increase the complexity of the pharmacophore is one way to avoid unfavorable effects arising from promiscuous interactions. 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

Ekins S. Predicting undesirable drug interactions with promiscuous proteins in silico. Drug Discov Today 2004 Mar 15 9(6) 276-85. Review. 

A measure of the promiscuity of these diacids was attempted with pyrimidine 26 vs pyrazine 20. The two heterocycles differ in size, shape and also basicity in addition, stacking interactions can be observed in the pyrimidine complex but not with pyrazine. These four variables make interpretation with confidence somewhat futile since it is difficult to attribute the binding differences to any particular feature. 

O Sullivan D, et al. On the interaction of promiscuous antigenic peptides with different DR alleles. Identification of common structural motifs. J Immunol 1991 147 2663. 

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