Membrane-bound drug targets

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

Many known drug receptors, and many prospective drug targets, exist as molecular arrays within membrane-bound macromolecules that cannot be readily crystallized neither can they be isolated or purified for the application of NMR methods. Moreover, even if an amino acid sequence were available, rule-based methods for the prediction of secondary structure, being derived as they are from a database of soluble proteins, cannot be applied with any confidence to the membrane-bound state. 

While the technique of X-ray crystallography is a complex instrumental and computational procedure, it can reveal the structure of very large macromolecules, which means that it permits the determination of the structure of both cytoplasmic proteins and membrane-bound proteins (proteins that are typically drug targets). While X-ray crystallography is very useful, however, it should be emphasized that proteins studied in this manner are in a crystalline state, a state that does not resemble the normal physiological (liquid) environment of the cell or body (Wishart, 2005). 

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