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Fragmental modeling of hPepT2 and analysis of its binding features by docking studies and pharmacophore mapping.
Bioorg Med Chem
Dipartimento di Scienze Farmaceutiche 'Pietro Pratesi', Facoltà di Farmacia, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133 Milano, Italy.
Published: August 2011
Over the last years, considerable progress has been made for the identification and characterization of drug transporters, and several modeling studies have been undertaken to predict their effects on ADME profiling. Thus, this study was focused on the peptide transporter hPepT2, which influences the regional pharmacokinetics in brain, the reabsorption from renal tubular fluid and the pulmonary delivery. A reliable model for hPepT2 was generated by fragments based on the resolved structure of the homologue lactose permease LacY and the structure is made available as Supplementary data. The interaction capacities of such a model were explored by docking a set of 75 known ligands. Docking results underlined the predilection of hPepT2 for highly hydrophobic ligands and the key role of ionic interactions elicited by both charged termini. The docking results were further verified developing a pharmacophore model which clarified the key features required for an optimal hPepT2 affinity and confirmed the main factors governing the hPepT2/hPepT1 selectivity. The soundness of the docking results and the agreement with the pharmacophore mapping afford an encouraging validation for the proposed hPepT2 model and suggest that it can be conveniently exploited to design peptide-like molecules with an improved affinity for this transporter.
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| http://dx.doi.org/10.1016/j.bmc.2011.06.027 | DOI Listing |
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