Discovery of Chemokine CXCL12 Inhibitors by Tandem Application of Virtual Screening and NMR Spectrometry

The CXC chemokine ligand CXCL12 and its receptor CXCR4 play critical roles in stem-cell homing, infectious diseases, and cancer, which led the CXCL12/CXCR4 signaling axis to attract much attention in drug discovery. CXCR4 is regarded as the primary target while CXCL12 is considered too small to be a druggable target. In this paper, we employed virtual screening approaches and ligand-based NMR screening methods from a SPECS library and in-house natural products to discover new CXCR12 inhibitors. Four natural triterpene saponins were confirmed, and the triterpene sapogenin was identified as the main binding epitope by saturation transfer difference-nuclear magnetic resonance and molecular docking studies. The pentacyclic triterpene scaffold and its elucidated structure-activity relationships provide a new and valuable research direction for the development of novel CXCL12 inhibitors.