- Authors:
-
- Våbenø, Jon ;
- Nielsen, Carsten Uhd ;
- Steffansen, Bente ;
- Lejon, Tore ;
- Sylte, Ingebrigt ;
-
Jørgensen, Flemming Steen
;
Close
0000-0001-8040-2998
Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet - Luthman, Kristina
- Subtitle:
- implications for design of hPEPT1 targeted prodrugs
- DOI:
- 10.1016/j.bmc.2005.01.019
- 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)
- Type:
- Journal article
- Language:
- English
- Published in:
- Bioorganic and Medicinal Chemistry, 2005, Vol 13, Issue 6, p. 1977-88
- Keywords:
- Amination; Dipeptides; Drug Design; Humans; Intestines; Ligands; Molecular Structure; Prodrugs; Symporters; Water; beta-Lactams
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2005
- Scientific Level:
- Scientific
- ID:
- 117464596
Checking for on-site access...
