Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs
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Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter : implications for design of hPEPT1 targeted prodrugs. / Våbenø, Jon; Nielsen, Carsten Uhd; Steffansen, Bente; Lejon, Tore; Sylte, Ingebrigt; Jørgensen, Flemming Steen; Luthman, Kristina.
In: Bioorganic & Medicinal Chemistry, Vol. 13, No. 6, 2005, p. 1977-88.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter
T2 - implications for design of hPEPT1 targeted prodrugs
AU - Våbenø, Jon
AU - Nielsen, Carsten Uhd
AU - Steffansen, Bente
AU - Lejon, Tore
AU - Sylte, Ingebrigt
AU - Jørgensen, Flemming Steen
AU - Luthman, Kristina
PY - 2005
Y1 - 2005
N2 - 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)
AB - 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)
KW - Amination
KW - Dipeptides
KW - Drug Design
KW - Humans
KW - Intestines
KW - Ligands
KW - Molecular Structure
KW - Prodrugs
KW - Symporters
KW - Water
KW - beta-Lactams
U2 - 10.1016/j.bmc.2005.01.019
DO - 10.1016/j.bmc.2005.01.019
M3 - Journal article
C2 - 15727852
VL - 13
SP - 1977
EP - 1988
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 6
ER -
ID: 38393823