title: Discovery of ligands for the human intestinal Di-/Tripeptide transporter (hPEPT1) using a QSAR-assisted virtual screening strategy.
abstract: The discovery of novel ligands for the hPEPT1 transporter is reported. By exploiting a fast and rigorously validated QSAR model in combination with the distance in activity-centered chemical space (DACCS) approach, a database of commercially available compounds (Sigma-Aldrich) was screened for virtual hits. Twelve compounds were then purchased and characterized in an apical [14C]Gly-Sar uptake competition assay. Four compounds displayed affinity in the medium-to-high range. A simple benzophenone derivative displayed high affinity with a sub-millimolar binding constant (Ki=0.24 mM). The results of this study will serve as starting points for future projects, including the design and synthesis of compound libraries that seek to systematically explore the fundamental requirements for binding and transport by hPEPT1.
authors: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors: Simon Birksø
authors: SB
authors: Larsen
authors: Diana Højmark
authors: DH
authors: Omkvist
authors: Birger
authors: B
authors: Brodin
authors: Carsten Uhd
authors: CU
authors: Nielsen
authors: Bente
authors: B
authors: Steffansen
authors: Lars
authors: L
authors: Olsen
authors: Flemming Steen
authors: FS
authors: Jørgensen
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000737:chemistry; D002460:Cell Line; D016208:Databases, Factual; D004285:Dogs; D006801:Humans; D008024:Ligands; D000074011:Peptide Transporter 1; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001577:Benzophenones; D008024:Ligands; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D054852:Small Molecule Libraries; D027981:Symporters; C047723:benzophenone