Discovery of ligands for the human intestinal Di-/Tripeptide transporter (hPEPT1) using a QSAR-assisted virtual...

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.