Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs

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

SN - 0968-0896

VL - 13

SP - 1977

EP - 1988

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 6

ER -