Modeling of the intestinal peptide transporter hPepT1 and analysis of its transport capacities by docking and pharmacophore mapping.

An early pharmacokinetic screen for peptidomimetic drugs should have the ability to predict molecules with high affinity for intestinal transporters, as peptide-like derivatives are seldom absorbed passively. Hence, the first objective of this study was to generate a reliable model for the structure of the hPepT1 protein, which is the main intestinal transporter involved in the absorption of both dietary peptides and peptidomimetics. The modeling was based on the resolved structure of the homologous bacterial lactose permease LacY using a fragmental strategy. The interaction capacities of the hPepT1 model were explored by docking a set of 50 known ligands. Despite the known predilection of hPepT1 for hydrophobic ligands, docking results unveiled the key role of the polar interactions stabilized by charged termini, especially concerning the ammonium head group. The docking results were further verified by developing a pharmacophore model that confirmed the key features required for optimal hPepT1 affinity. The consistency of the docking results and the agreement with the pharmacophore model afford an encouraging validation for the proposed model and suggest that it can be exploited to design peptide-like molecules with an improved affinity for such a transporter.