Optimized method of G-protein-coupled receptor homology modeling: its application to the discovery of novel CXCR7 ligands

J Med Chem. 2013 Jun 13;56(11):4236-51. doi: 10.1021/jm400307y. Epub 2013 May 29.


Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimized GPCR structure modeling method based on multiple GPCR crystal structures. This method was designed to be applicable to distantly related receptors of known structural templates. CXC chemokine receptor (CXCR7) is a potential drug target for cancer chemotherapy. Homology modeling, docking, and virtual screening for CXCR7 were carried out using our method. The predicted docking poses of the known antagonists were different from the crystal structure of human CXCR4 with the small-molecule antagonist IT1t. Furthermore, 21 novel CXCR7 ligands with IC50 values of 1.29-11.4 μM with various scaffolds were identified by structure-based virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Protein Conformation
  • Radioligand Assay
  • Receptors, CXCR / antagonists & inhibitors
  • Receptors, CXCR / chemistry*
  • Receptors, CXCR / metabolism
  • Receptors, CXCR4 / chemistry
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship


  • ACKR3 protein, human
  • CXCR4 protein, human
  • Ligands
  • Receptors, CXCR
  • Receptors, CXCR4
  • Small Molecule Libraries