title: Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs.
abstract: The aim of the present study was to develop a computational method aiding the design of dipeptidomimetic pro-moieties targeting the human intestinal di-/tripeptide transporter hPEPT1. First, the conformation in which substrates bind to hPEPT1 (the bioactive conformation) was identified by conformational analysis and 2D dihedral driving analysis of 15 hPEPT1 substrates, which suggested that psi(1) approximately 165 degrees , omega(1) approximately 180 degrees , and phi(2) approximately 280 degrees were descriptive of the bioactive conformation. Subsequently, the conformational energy required to change the peptide backbone conformation (DeltaE(bbone)) from the global energy minimum conformation to the identified bioactive conformation was calculated for 20 hPEPT1 targeted model prodrugs with known K(i) values. Quantitatively, an inverse linear relationship (r(2)=0.81, q(2)=0.80) was obtained between DeltaE(bbone) and log1/K(i), showing that DeltaE(bbone) contributes significantly to the experimentally observed affinity for hPEPT1 ligands. Qualitatively, the results revealed that compounds classified as high affinity ligands (K(i)<0.5 mM) all have a calculated DeltaE(bbone)<1 kcal/mol, whereas medium and low-affinity compounds (0.5 mM<K(i)<15 mM) have DeltaE(bbone) values in the range 1-3 kcal/mol. The findings also shed new light on the basis for the experimentally observed stereoselectivity of hPEPT1.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacy, University of Tromsø, N-9037 Tromsø, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Våbenø
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
authors.forename: Bente
authors.initials: B
authors.lastname: Steffansen
authors.forename: Tore
authors.initials: T
authors.lastname: Lejon
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Flemming Steen
authors.initials: FS
authors.lastname: Jørgensen
authors.forename: Kristina
authors.initials: K
authors.lastname: Luthman
mesh_terms: D000586:Amination; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007422:Intestines / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D027981:Symporters / Q000737:chemistry* / Q000378:metabolism*; D014867:Water / Q000737:chemistry; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D008024:Ligands; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters; D047090:beta-Lactams; D014867:Water