An NMR study of conformations of substituted dipeptides in dodecylphosphocholine micelles: Implications for drug transport

Efficient transport of intact drug (solute) across the intestinal epitheliu m is typically a requirement for good oral activity. In general, the membra ne permeability of a solute is a complex function of its size, lipophilicit y, hydrogen bond potential, charge, and conformation. In conjunction with t heoretical/computational and in vitro drug transport studies, seven dipepti de (R-1-D-Xaa-D-Phe-NHMe) homologues were each dissolved in a micellar d(38 )-dodecylphosphocholine solvent system. In this homologous dipeptide series , factors such as size, lipophilicity, hydrogen-bond potential, and charge were either tightly controlled or well-characterized by other methods in or der to investigate by nmr how conformational factors relate to transport. N uclear Overhauser effect spectroscopy experiments and amide-NH-H2O chemical exchange rates showed that the five more lipophilic dipeptides were predom inately associated with micelle, whereas the two less lipophilic analogues were not. Rotating frame nuclear Overhauser effect spectroscopy derived int erproton distance restraints for each analogue, along with (3)J(HH)-derived dihedral restraints, were used in molecular dynamics/simulated annealing c omputations. Our results suggest that-other factors being equal-flexible di peptides having a propensity to fold together nonpolar N- and C-terminal mo ieties allow greater segregation of polar and nonpolar domains and may poss ess enhanced transport characteristics. Dipeptides that were less flexible or that retained a less amphiphilic conformation did not have comparably en hanced transport characteristics. We suggest that these conformational/tran sport correlations may hold true for small, highly functionalized solutes ( drugs) in general. (C) 2000 John Wiley & Sons, Inc.