Bioactive substrate transport

The quantity Aimf on which both transport and receptor binding of a bioactive substrate depend is variable in composition. It depends on the nature of the atoms or groups of atoms which make up the membrane surface or alternatively the receptor surface. 

So far, SAR studies for P-gp have been performed on the basis of classical QSAR principles which were designed for transporters or receptors, which naturally bind one specific substrate from an aqueous environment. The assumptions made are that (i) the modeled conformation is the bioactive one (ii) the binding site and/or mode is the same for all modeled compounds (iii) interactions between the drug and the binding site are mainly due to enthalpic processes (e.g., van der Waals interactions) and (iv) solvent or membrane effects are negligible (cf. Ref. [35]). 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

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